SPAST

Summary

SPAST (spastin, HGNC:11233) is a protein-coding gene on chromosome 2p22.3, encoding Spastin (Q9UBP0). ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The use of alternative translational initiation sites in this gene results in a single transcript variant that can produce isoforms that differ in the length of their N-terminus and which thereby differ in the efficiency of their export from the nucleus to the cytoplasm. In addition, alternative splicing results in multiple transcript variants that encode isoforms that differ in other protein regions as well. One isoform of this gene has been shown to be a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution. Mutations in this gene cause the most frequent form of autosomal dominant spastic paraplegia 4.

Source: NCBI Gene 6683 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 4 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,639 total — 510 pathogenic, 153 likely-pathogenic (top 1% of genes corpus-wide)
• GTEx eGene: eQTL in 15 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 40
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.11 (intermediate), LOEUF 0.69 (unconstrained)
• MANE Select transcript: NM_014946
• Interaction hub: 2,156 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11233
Approved symbol	SPAST
Name	spastin
Location	2p22.3
Locus type	gene with protein product
Status	Approved
Aliases	FSP2, ADPSP, KIAA1083
Ensembl gene	ENSG00000021574
Ensembl biotype	protein_coding
OMIM	604277
Entrez	6683

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 19 protein_coding, 9 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000315285

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2

ENST00000315285, ENST00000621856, ENST00000642281, ENST00000642455, ENST00000642751, ENST00000642999, ENST00000643327, ENST00000644408, ENST00000644954, ENST00000645159, ENST00000645400, ENST00000645550, ENST00000645671, ENST00000645730, ENST00000646082, ENST00000646571, ENST00000647007, ENST00000647133, ENST00000704289, ENST00000713714, ENST00000713715, ENST00000713716, ENST00000713718, ENST00000713719, ENST00000933131, ENST00000933132, ENST00000933133, ENST00001031264, ENST00001085491, ENST00001085492, ENST00001117555

RefSeq mRNA: 5 — MANE Select: NM_014946 NM_001363823, NM_001363875, NM_001377959, NM_014946, NM_199436

CCDS: CCDS1778, CCDS1779, CCDS86830, CCDS92732

Canonical transcript exons

ENST00000315285 — 17 exons

Exon	Start	End
ENSE00001070179	32087492	32087578
ENSE00001070181	32089522	32089605
ENSE00003815281	32063556	32064246
ENSE00004020827	32154374	32157637
ENSE00004020830	32141904	32141946
ENSE00004020833	32114638	32114825
ENSE00004020836	32144937	32145007
ENSE00004020841	32136877	32136968
ENSE00004020847	32137109	32137188
ENSE00004020850	32147218	32147258
ENSE00004020853	32136563	32136638
ENSE00004020855	32143336	32143415
ENSE00004020856	32128408	32128479
ENSE00004020858	32126948	32127022
ENSE00004020860	32115702	32115835
ENSE00004020862	32098796	32098891
ENSE00004020865	32116119	32116212

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 96.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.4849 / max 266.9382, expressed in 1811 samples.

Highest expression (Bgee): cortical plate, oocyte, secondary oocyte, ganglionic eminence, calcaneal tendon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

SPAST is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 15 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

18 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	2.2e-08	-0.18	2:32183560:T:C
Adipose Subcutaneous	eqtl	4.2e-05	+0.13	2:32033467:G:C
Cells EBV-transformed lymphocytes	eqtl	9.2e-05	-0.21	2:32269893:A:C
Muscle Skeletal	eqtl	4.0e-04	-0.07	2:32461514:A:G
Thyroid	eqtl	7.5e-04	+0.13	2:32148229:C:T
Skin Sun Exposed Lower leg	eqtl	1.1e-03	-0.13	2:31553069:A:C
Colon Transverse	eqtl	1.8e-03	+0.14	2:32102685:G:A
Pituitary	eqtl	2.6e-03	+0.18	2:32026040:G:A
Muscle Skeletal	sqtl	1.2e-02	+0.26	2:32693653:G:A
Brain Caudate basal ganglia	eqtl	1.4e-02	-0.20	2:31799063:C:T
Adipose Subcutaneous	sqtl	1.4e-02	+0.27	2:32299843:G:A
Skin Not Sun Exposed Suprapubic	eqtl	1.5e-02	-0.27	2:31258474:C:T
Lung	eqtl	1.8e-02	+0.09	2:31791608:A:G
Colon Sigmoid	eqtl	2.2e-02	-0.13	2:32268141:T:C
Thyroid	sqtl	3.3e-02	+0.97	2:32507685:A:G
Esophagus Mucosa	eqtl	3.5e-02	-0.11	2:31517792:T:A
Breast Mammary Tissue	eqtl	4.6e-02	-0.11	2:32264782:T:C
Artery Tibial	eqtl	5.0e-02	+0.22	2:32156895:C:T

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
19630	13.4775	1791
19626	2.1480	1054
19628	1.8650	945
19627	0.6924	335
19629	0.2405	126
19631	0.0616	24

Top tissues by expression

showing 100 of 296 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.27	gold quality
oocyte	CL:0000023	95.65	gold quality
secondary oocyte	CL:0000655	94.72	gold quality
ganglionic eminence	UBERON:0004023	94.22	gold quality
calcaneal tendon	UBERON:0003701	92.24	gold quality
palpebral conjunctiva	UBERON:0001812	91.78	gold quality
epithelium of nasopharynx	UBERON:0001951	91.39	gold quality
ventricular zone	UBERON:0003053	91.21	gold quality
germinal epithelium of ovary	UBERON:0001304	91.08	gold quality
embryo	UBERON:0000922	90.77	gold quality
endothelial cell	CL:0000115	90.51	gold quality
tibia	UBERON:0000979	90.38	gold quality
esophagus squamous epithelium	UBERON:0006920	87.90	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.82	gold quality
amniotic fluid	UBERON:0000173	87.80	gold quality
monocyte	CL:0000576	87.06	gold quality
mononuclear cell	CL:0000842	86.91	gold quality
leukocyte	CL:0000738	86.78	gold quality
corpus callosum	UBERON:0002336	86.67	gold quality
parietal pleura	UBERON:0002400	85.35	gold quality
jejunal mucosa	UBERON:0000399	85.31	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.17	gold quality
adrenal tissue	UBERON:0018303	85.12	gold quality
pleura	UBERON:0000977	84.61	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.60	gold quality
Brodmann (1909) area 23	UBERON:0013554	84.53	gold quality
visceral pleura	UBERON:0002401	84.52	gold quality
spinal cord	UBERON:0002240	84.22	gold quality
islet of Langerhans	UBERON:0000006	84.20	gold quality
substantia nigra pars reticulata	UBERON:0001966	84.07	gold quality
substantia nigra pars compacta	UBERON:0001965	83.61	gold quality
bone marrow cell	CL:0002092	83.48	gold quality
squamous epithelium	UBERON:0006914	83.43	gold quality
blood	UBERON:0000178	83.41	gold quality
upper leg skin	UBERON:0004262	83.02	gold quality
primary visual cortex	UBERON:0002436	82.93	gold quality
cranial nerve II	UBERON:0000941	82.91	gold quality
hair follicle	UBERON:0002073	82.66	gold quality
tonsil	UBERON:0002372	82.52	gold quality
prefrontal cortex	UBERON:0000451	82.50	gold quality
gingival epithelium	UBERON:0001949	82.25	gold quality
skin of hip	UBERON:0001554	82.15	gold quality
colonic epithelium	UBERON:0000397	82.07	gold quality
epithelium of esophagus	UBERON:0001976	81.71	gold quality
gastrocnemius	UBERON:0001388	81.55	gold quality
choroid plexus epithelium	UBERON:0003911	81.50	gold quality
muscle of leg	UBERON:0001383	81.46	gold quality
endometrium	UBERON:0001295	81.40	gold quality
stromal cell of endometrium	CL:0002255	81.36	gold quality
rectum	UBERON:0001052	81.21	gold quality
lateral globus pallidus	UBERON:0002476	81.13	gold quality
substantia nigra	UBERON:0002038	80.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.80	gold quality
duodenum	UBERON:0002114	80.74	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	80.58	gold quality
midbrain	UBERON:0001891	80.37	gold quality
occipital lobe	UBERON:0002021	80.36	gold quality
pigmented layer of retina	UBERON:0001782	80.35	gold quality
cerebellar cortex	UBERON:0002129	80.24	gold quality
inferior vagus X ganglion	UBERON:0005363	80.21	gold quality
cerebellar hemisphere	UBERON:0002245	80.17	gold quality
bone marrow	UBERON:0002371	80.16	gold quality
tendon	UBERON:0000043	80.05	gold quality
amygdala	UBERON:0001876	80.04	gold quality
mucosa of sigmoid colon	UBERON:0004993	79.94	gold quality
Ammon’s horn	UBERON:0001954	79.93	gold quality
cerebral cortex	UBERON:0000956	79.87	gold quality
jejunum	UBERON:0002115	79.86	gold quality
neocortex	UBERON:0001950	79.73	gold quality
granulocyte	CL:0000094	79.68	gold quality
gingiva	UBERON:0001828	79.64	gold quality
cerebellum	UBERON:0002037	79.56	gold quality
central nervous system	UBERON:0001017	79.43	gold quality
telencephalon	UBERON:0001893	79.41	gold quality
lymph node	UBERON:0000029	79.28	gold quality
brain	UBERON:0000955	79.27	gold quality
frontal cortex	UBERON:0001870	79.22	gold quality
frontal lobe	UBERON:0016525	79.22	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.04	gold quality
forebrain	UBERON:0001890	78.96	gold quality
pancreas	UBERON:0001264	78.88	gold quality
hypothalamus	UBERON:0001898	78.80	gold quality
gall bladder	UBERON:0002110	78.78	gold quality
vermiform appendix	UBERON:0001154	78.77	gold quality
putamen	UBERON:0001874	78.76	gold quality
cingulate cortex	UBERON:0003027	78.74	gold quality
hindlimb stylopod muscle	UBERON:0004252	78.74	gold quality
nucleus accumbens	UBERON:0001882	78.73	gold quality
caudate nucleus	UBERON:0001873	78.70	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	78.64	gold quality
anterior cingulate cortex	UBERON:0009835	78.57	gold quality
temporal lobe	UBERON:0001871	78.56	gold quality
subthalamic nucleus	UBERON:0001906	78.53	gold quality
lateral nuclear group of thalamus	UBERON:0002736	78.49	gold quality
blood vessel layer	UBERON:0004797	78.25	gold quality
right frontal lobe	UBERON:0002810	78.17	gold quality
colonic mucosa	UBERON:0000317	78.15	gold quality
ovary	UBERON:0000992	78.03	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	77.87	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.64
E-MTAB-6386	no	84.36

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Corpus callosum	tissue	57.7
Spinal cord	tissue	49.6
Midbrain	tissue	46.9
Pons	tissue	45.1
Medulla oblongata	tissue	45.1
Thalamus	tissue	44.2
Substantia nigra	tissue	43.3
Cerebellum	tissue	41.1	high
Hippocampal formation	tissue	39.7
Putamen	tissue	39.4
Superior colliculi	tissue	39.3
Hypothalamus	tissue	39.2
Periaqueductal gray	tissue	38.0
Cerebral cortex	tissue	35.7	medium
Occipital cortex	tissue	35.7
Motor cortex	tissue	35.5
Septum	tissue	34.4
Somatosensory cortex	tissue	34.3
Ventral forebrain	tissue	34.1
Prefrontal cortex	tissue	33.7
Entorhinal cortex	tissue	33.2
Retrosplenial and cingulate cortex	tissue	31.9
Retrosplenial cortex	tissue	31.7
Olfactory bulb	tissue	31.5
Temporal cortex	tissue	30.8
Amygdala	tissue	30.1
Insular cortex	tissue	30.0
Basal ganglia	tissue	28.6	medium
Locus coeruleus	tissue	23.8
Frontal cortex	tissue	23.0
Caudate putamen	tissue	21.6
Hippocampus	tissue	20.1	low
Nucleus accumbens	tissue	19.8
Postcentral gyrus	tissue	18.7
Thymus	tissue	13.1
Bone marrow	tissue	9.7	medium
Testis	tissue	9.4	medium
Lymph node	tissue	9.3	high
Tongue	tissue	9.3
Liver	tissue	8.9	medium
Ovary	tissue	8.8	medium
Tonsil	tissue	8.6	high
Thyroid gland	tissue	8.2	medium
Cervix	tissue	8.1	medium
Choroid plexus	tissue	8.0
Small intestine	tissue	7.6	high
Skeletal muscle	tissue	7.4	high
Endometrium 1	tissue	7.3	medium
Duodenum	tissue	7.1	high
Skin 1	tissue	7.0	low
Rectum	tissue	7.0	high
Urinary bladder	tissue	7.0	medium
Appendix	tissue	7.0	medium
Smooth muscle	tissue	6.9	medium
Retina	tissue	6.7
Esophagus	tissue	6.7	medium
Colon	tissue	6.7	high
Spleen	tissue	6.7	high
Placenta	tissue	6.4	medium
Gallbladder	tissue	6.2	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — White matter (57.7), Ventral spinal cord (49.6), Dorsal spinal cord (44.8), Dorsal hippocampus (39.7), Ventral hippocampus (35.3).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELK1, HOXA10, MYC, NRF1, SOX11

miRNA regulators (miRDB)

Targeting SPAST by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 160 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170

Functional genomics

gnomAD constraint: pLI 0.115, LOEUF 0.69, missense Z 0.23 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000315285 splits into 3 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:32,063,832–32,116,142	543 / 445.2	1.22	no
2:32,116,143–32,141,934	78 / 197.6	0.39	no
2:32,141,935–32,154,493	96 / 127.6	0.75	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• second leaky splice-site mutation in hereditary spastic paraplegia (PMID:11704932)
• may be involved in microtubule dynamics similarly to the highly homologous microtubule-severing protein, katanin; Impairment of fine regulation of the microtubule cytoskeleton in long axons, due to spastin mutations, may underlie pathogenesis of HSP. (PMID:11809724)
• A novel mutation in the spastin gene in a family with spastic paraplegia. (PMID:12023066)
• Novel mutations of SPG4 in patients with autosomal dominant hereditary spastic paraplegia are located mainly in the conserved AAA cassette-encoding region of the spastin gene. (PMID:12124993)
• Five spastin gene mutations have been detected in Japanese with hereditary spastic paraplegia, three of which are novel. (PMID:12161613)
• Three novel spastin (SPG4) mutations in families with autosomal dominant hereditary spastic paraplegia. (PMID:12163196)
• Autosomal dominant (AD) pure spastic paraplegia (HSP) linked to locus SPG4 affects almost exclusively males in a large pedigree (PMID:12471215)
• Mutations of spastin are responsible for the most common autosomal dominant form of hereditary spastic paraplegia (PMID:12490534)
• Eight SPG4 mutations, seven of which are novel, have been identified in pure autosomal dominant spastic paraplegia patients. (PMID:12552568)
• A novel insertion mutation in spastin gene is the cause of spastic paraplegia in a Chinese (PMID:12736085)
• mutation in spastin and paraplegin genes does not appear to cause motor neuron disease (PMID:14506940)
• The abnormal interaction of mutant spastin with microtubules is demonstrated to be associated with an abnormal perinuclear clustering of mitochondria and peroxisomes, suggestive of an impairment of kinesin-mediated intracellular transport. (PMID:14681884)
• The percentage of involved Chinese families with autosomal dominant hereditary spastic paraplegia with an SPG4 mutation is 18% (4/22), lower than the estimated 40% linked to this lo (PMID:14732620)
• A variant form of hereditary spastic paraplegia & congenital arachnoid cysts has an new autosomal dominant mutation, T614I, in exon 17 of SPG4. It may play a role in both focal cortical dysgenesis & corticospinal motoneuron neurodegeneration. (PMID:15159500)
• spastin phosphorylation by Cdks has a role in the neurodegeneration of the most-common form of hereditary spastic paraplegia (PMID:15248095)
• Spastin interacts with the centrosomal protein NA14, and co-fractionates with gamma-tubulin, a centrosomal marker. (PMID:15269182)
• 2 codominant mutations of different SPG4 alleles (P361L & S44L)resulted in a more severe phenotype. P361L is a new mutation near the beginning of the AAA casette. (PMID:15326248)
• This study detected two novel missense mutations, 1375A > G (R459G) and 1378C > T (R460C) in the patient with autosomal dominant hereditary spastic paraplegia (PMID:15482961)
• A novel SPG4-nonsense-mutation (p.Leu239X trancation) in a large German pedigree with pure spastic paraplegia. (PMID:15739043)
• Eleven novel mutations within the SPG4 gene are associated with autosomal dominant hereditary spastic paraplegia (AD-HSP). (PMID:15841487)
• A novel SPG4 906delT frame-shift mutation in exon 6 was identified in a large Italian family with an autosomal dominant form of hereditary spastic paraplegia (ADHSP). (PMID:15858810)
• Spastin plays a role in microtubule dynamics, with a crucial role in microtubule organization in spastic paraplegia. (PMID:15891913)
• Reduced regional cerebral blood flow in SPG4-linked hereditary spastic paraplegia. (PMID:15939438)
• We propose that sequence alterations of spastin may comprise a genetic risk factor in a greater spectrum of motor neuron disorders including clinical variants of ALS. (PMID:16009903)
• Data show that spastin function is modulated through usage of alternative translational start sites and active nuclear import and export, opening new perspectives for the pathogenesis of hereditary spastic paraplegia (PMID:16026783)
• SPG4 gene mutations in patients with sporadic spastic paraplegia suggests that gene testing should be done in individuals with pure or complicated spastic paraplegia without family histories. (PMID:16055926)
• spastin mutations are a frequent cause of apparently sporadic spastic paraparesis but not of primary lateral sclerosis (PMID:16240363)
• Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners. (PMID:16339213)
• Data demonstrate that reticulon 1 interacts specifically with spastin. (PMID:16602018)
• The frequency for SPG4 mutations detected in autosomal dominant hereditary spastic paraplegia was 44.4%. This study contributes to expand the spectrum of SPG4 mutations in Italian population. (PMID:16684598)
• These results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant Hereditary spastic paraplegia (HSP), although SPAST mutations are also observed in patients with sporadic spastic paraplegia. (PMID:16788734)
• Interaction between spastin and atlastin may define a cellular biological pathway that is important in axon maintenance, the failure of which may be pathogenetically relevant. (PMID:16815977)
• The demonstration of spastin in functionally different brain regions may provide neuroanatomical basis to explain why different brain disorders and cognitive impairment occur in patients with spastin mutation. (PMID:16828199)
• Partial SPAST deletions represent an underestimated cause of autosomal dominant hereditary spastic paraplegia. Partial SPAST deletions are likely to act via haploinsufficiency. (PMID:17035675)
• 16 different heterozygotic spg4 exon deletions were found. Exon deletions in SPG4 are as frequent as point mutations. (PMID:17098887)
• The clinical course of hereditary spastic paraplegia is related to the type of the spastin gene mutation. (PMID:17100993)
• data implies that for SPAST, in contrast to many other genes, large genomic deletions together with the long recognized alterations in or near the coding sequences represent the complete spectrum of hereditary spastic paraplegia-causing mutations (PMID:17345589)
• Given that Spastin engages the MT in two places, we propose that severing occurs by forces exerted on the C-terminal tail of tubulin, which results in a conformational change in tubulin, which releases it from the polymer. (PMID:17389232)
• The studied kindred has typical clinical manifestations of hereditary spastic paraplegia. The pathogenesis has no association with mutation of the exons of spastin gene. (PMID:17407089)
• Genotyping two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of Hereditary Spastic Paraplegia [including spastin] play a role in susceptibility to MS or modifying the course of MS (PMID:17420921)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	spast	ENSDARG00000024933
mus_musculus	Spast	ENSMUSG00000024068
rattus_norvegicus	Spast	ENSRNOG00000027136
drosophila_melanogaster	spas	FBGN0039141
caenorhabditis_elegans		WBGENE00016045

Paralogs (9): KATNAL1 (ENSG00000102781), VPS4B (ENSG00000119541), FIGNL1 (ENSG00000132436), VPS4A (ENSG00000132612), ATAD1 (ENSG00000138138), KATNAL2 (ENSG00000167216), FIGN (ENSG00000182263), KATNA1 (ENSG00000186625), FIGNL2 (ENSG00000261308)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1858896) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 33 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal gait	3
abnormal axon morphology	3
small testis	1
seminiferous tubule degeneration	1
abnormal spermatogenesis	1
decreased body weight	1
impaired coordination	1
short stride length	1
hydrocephaly	1
infertility	1
male infertility	1
abnormal spermiogenesis	1
abnormal brain morphology	1
aneuploidy	1
abnormal axonal transport	1
decreased testis weight	1
azoospermia	1
abnormal male meiosis	1
abnormal spermatid morphology	1
arrest of male meiosis	1
abnormal acrosome morphology	1
abnormal sperm nucleus morphology	1
abnormal manchette morphology	1
ectopic manchette	1
abnormal meiotic spindle morphology	1

+8 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Drosophila sechellia	B4HGG6	99.8%	Diamond
Bos taurus	F6QV99	99.7%	Diamond
Drosophila simulans	B4QSF0	99.5%	Diamond
Pongo abelii	Q5R658	99.5%	Diamond
Papio anubis	A9RA82	99.2%	Diamond
Macaca fascicularis	Q4R407	99.2%	Diamond
Drosophila persimilis	B4G437	99.1%	Diamond
Drosophila pseudoobscura pseudoobscura	Q298L4	99.1%	Diamond
Drosophila erecta	B3P8A3	98.9%	Diamond
Drosophila yakuba	B4PL32	98.8%	Diamond
Oryctolagus cuniculus	B7NZ88	97.8%	Diamond
Sorex araneus	B3EX35	96.7%	Diamond
Otolemur garnettii	B4USW8	96.7%	Diamond
Xenopus tropicalis	Q0IIR9	95.7%	Diamond
Xenopus laevis	Q9PUL2	95.7%	Diamond
Sus scrofa	D3K5L7	94.6%	Diamond
Canis lupus familiaris	E2R222	94.6%	Diamond
Drosophila ananassae	B3M301	91.1%	Diamond
Drosophila mojavensis	B4K799	90.7%	Diamond
Drosophila virilis	B4M0H8	90.7%	Diamond
Drosophila willistoni	B4NBP4	87.3%	Diamond
Drosophila grimshawi	B4JII0	87.0%	Diamond
Gallus gallus	Q1HGK7	85.6%	Diamond
Salmo salar	B5X3X5	82.4%	Diamond
Caenorhabditis briggsae	Q60QD1	76.9%	Diamond
Bombyx mori	D0FH76	76.7%	Diamond
Candida albicans SC5314	Q5AG40	76.0%	Diamond
Saccharomyces cerevisiae S288C	P52917	75.9%	Diamond
Arabidopsis thaliana	Q8H1F9	73.2%	Diamond
Schizosaccharomyces pombe 972h-	O43078	66.9%	Diamond
Strongylocentrotus purpuratus	O61577	62.7%	Diamond
Brugia malayi	A8QFF6	60.2%	Diamond
Dictyostelium discoideum	Q54KQ7	60.2%	Diamond
Anopheles gambiae	Q7QBW0	58.5%	Diamond
Ixodes scapularis	B7PXE3	58.3%	Diamond
Ignicoccus hospitalis KIN4/I	A8AC24	55.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SLC30A6	protein-coding	55676
DPY30	protein-coding	84661
MEMO1	protein-coding	51072
SLC30A6-DT	ncRNA	118568811
NLRC4	protein-coding	58484
YIPF4	protein-coding	84272

Protein

Protein identifiers

Spastin — Q9UBP0 (reviewed: Q9UBP0)

Alternative names: Spastic paraplegia 4 protein

All UniProt accessions (20): A0A2R8Y481, A0A2R8Y4I8, A0A2R8Y5N9, A0A2R8Y7K2, A0A2R8Y7W6, A0A2R8YCL5, A0A2R8YEA0, A0A2R8YFC9, A0A2R8YFW8, A0A2R8YGN6, A0A2U3TZR0, A0A994J6X4, A0AAQ5BGQ0, A0AAQ5BGQ4, A0AAQ5BGR4, A0AAQ5BGS6, A0AAQ5BGU3, E5KRP5, E5KRP6, Q9UBP0

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated. Preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold. Severing activity is not dependent on tubulin acetylation or detyrosination. Microtubule severing promotes reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. It is critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. SPAST is involved in abscission step of cytokinesis and nuclear envelope reassembly during anaphase in cooperation with the ESCRT-III complex. Recruited at the midbody, probably by IST1, and participates in membrane fission during abscission together with the ESCRT-III complex. Recruited to the nuclear membrane by IST1 and mediates microtubule severing, promoting nuclear envelope sealing and mitotic spindle disassembly during late anaphase. Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and endosome recycling. Recruited by IST1 to endosomes and regulates early endosomal tubulation and recycling by mediating microtubule severing. Probably plays a role in axon growth and the formation of axonal branches. Involved in lipid metabolism by regulating the size and distribution of lipid droplets.

Subunit / interactions. Homohexamer. Mostly monomeric, but assembles into hexameric structure for short periods of time. Oligomerization seems to be a prerequisite for catalytic activity. Binding to ATP in a cleft between two adjacent subunits stabilizes the homohexameric form. Binds to microtubules at least in part via the alpha-tubulin and beta-tubulin tails. The hexamer adopts a ring conformation through which microtubules pass prior to being severed. Does not interact strongly with tubulin heterodimers. Interacts (via MIT domain) with CHMP1B; the interaction is direct. Interacts with SSNA1. Interacts with ATL1. Interacts with RTN1. Interacts with ZFYVE27. Isoform 1 but not isoform 3 interacts with RTN2. Interacts with REEP1. Interacts (via MIT domain) with IST1.

Subcellular location. Membrane. Endoplasmic reticulum. Midbody. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Perinuclear region. Nucleus. Spindle. Cell projection. Axon Endoplasmic reticulum membrane. Nucleus membrane. Lipid droplet. Endosome Cytoplasm. Endosome.

Tissue specificity. Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle. The short isoforms may predominate in brain and spinal cord.

Disease relevance. Spastic paraplegia 4, autosomal dominant (SPG4) [MIM:182601] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosteric enzyme with a cooperative mechanism; at least two neighbor subunits influence each other strongly in spastin hexamers. Microtubule binding promotes cooperative interactions among spastin subunits. ATP-bound enzyme interacts strongly and cooperatively with microtubules; this interaction stimulates ATP hydrolysis.

Miscellaneous. Produced by alternative promoter usage. May also be produced by alternative initiation at Met-87 of isoform 1. Major isoform. Produced by alternative promoter usage and alternative splicing. May also be produced by alternative initiation at Met-87 of isoform 2.

Similarity. Belongs to the AAA ATPase family. Spastin subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UBP0-1	1, Long, Long variant 1, 68 kDa, M1	yes
Q9UBP0-2	2, Long variant 2
Q9UBP0-3	3, Short, Short variant 1, 60 kDa, M87
Q9UBP0-4	4, Short variant 2

RefSeq proteins (5): NP_001350752, NP_001350804, NP_001364888, NP_055761, NP_955468 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR007330	MIT_dom	Domain
IPR015415	Spast_Vps4_C	Domain
IPR017179	Spastin	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035106	Spastin_chordate	Family
IPR041569	AAA_lid_3	Domain
IPR050304	MT-severing_AAA_ATPase	Family

Pfam: PF00004, PF09336, PF17862

Enzyme classification (BRENDA)

• EC 5.6.1.1 — microtubule-severing ATPase (BRENDA: 21 organisms, 29 substrates, 57 inhibitors, 16 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0003–2.94	16

UniProt features (212 total): sequence variant 127, helix 27, mutagenesis site 15, region of interest 13, strand 6, turn 6, modified residue 4, short sequence motif 3, compositionally biased region 3, topological domain 2, splice variant 2, chain 1, intramembrane region 1, binding site 1, domain 1

Structure

Experimental structures (PDB)

7 structures by resolution:

PDB	Title	Method	Resolution (Å)
7S7J	Structure of Human SPASTIN-IST1 complex.	X-RAY DIFFRACTION	1.15
3EAB	Crystal structure of Spastin MIT in complex with ESCRT III	X-RAY DIFFRACTION	2.5
5Z6Q	Crystal structure of AAA of Spastin	X-RAY DIFFRACTION	3
5Z6R	SPASTIN AAA WITH ATP	X-RAY DIFFRACTION	3
3VFD	Human spastin AAA domain	X-RAY DIFFRACTION	3.3
6PEK	Structure of Spastin Hexamer (Subunit A-E) in complex with substrate peptide	ELECTRON MICROSCOPY	4.2
6PEN	Structure of Spastin Hexamer (whole model) in complex with substrate peptide	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBP0-F1	77.03	0.48

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Isomerase, Transporters, Transporter channels and pores, Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1)

Position	Role
382–389	ATP

Post-translational modifications (4)

Type	Positions
Phosphoserine	245, 268, 597
Phosphothreonine	306

Mutagenesis-validated functional residues (15)

Position	Phenotype
1	cytoplasmic and nuclear.
65	abolishes localization to lipid droplets.
81–84	does not affect localization to lipid droplets.
87	exclusively cytoplasmic.
120	impairs binding to chmp1b. impairs midbody localization; when associated with d-124.
124	impairs binding to chmp1b.
124	impairs binding to chmp1b. impairs midbody localization; when associated with d-120.
310–312	loss of microtubule-binding.
388	abrogates atpase activity and abolishes microtubule severing.
415	abrogates binding to the tail of alpha-tubulin and beta-3-tubulin, impairs atpase activity and abolishes microtubule severing.
442	abrogates atp hydrolysis, abolishes microtubule severing, stabilizes the homohexameric form, and promotes microtubule binding and …
448	abolishes atpase activity.
448	does not affect atpase activity.
451	abrogates binding to the tail of alpha-tubulin and beta-3-tubulin, impairs atpase activity and abolishes microtubule severing.
457	abrogates binding to the tail of alpha-tubulin and beta-3-tubulin and abolishes microtubule severing.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 7; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

7 pathways:

ID	Pathway	Evidence
R-HSA-9668328	Sealing of the nuclear envelope (NE) by ESCRT-III	curated
R-HSA-1640170	Cell Cycle	—
R-HSA-69278	Cell Cycle, Mitotic	—
R-HSA-68886	M Phase	—
R-HSA-68882	Mitotic Anaphase	—
R-HSA-2555396	Mitotic Metaphase and Anaphase	—
R-HSA-2995410	Nuclear Envelope (NE) Reassembly	—

MSigDB gene sets: 390 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_MITOTIC_CYTOKINESIS, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, TAATAAT_MIR126, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, MORF_MSH3, GOBP_MEMBRANE_BIOGENESIS, MORF_BRCA1, MORF_ATRX, GCM_ZNF198, GOBP_CELL_CYCLE_PHASE_TRANSITION, GCM_PPM1D, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN

GO Biological Process (23): mitotic cytokinesis (GO:0000281), microtubule bundle formation (GO:0001578), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), mitotic nuclear membrane reassembly (GO:0007084), anterograde axonal transport (GO:0008089), exit from mitosis (GO:0010458), axonal transport of mitochondrion (GO:0019896), central nervous system neuron axonogenesis (GO:0021955), positive regulation of microtubule depolymerization (GO:0031117), nuclear membrane reassembly (GO:0031468), positive regulation of cytokinesis (GO:0032467), cytokinetic process (GO:0032506), protein hexamerization (GO:0034214), microtubule severing (GO:0051013), mitotic spindle disassembly (GO:0051228), protein homooligomerization (GO:0051260), cytoskeleton-dependent cytokinesis (GO:0061640), membrane fission (GO:0090148), microtubule cytoskeleton organization (GO:0000226), nervous system development (GO:0007399), axonogenesis (GO:0007409), cell differentiation (GO:0030154), cell division (GO:0051301)

GO Molecular Function (11): ATP binding (GO:0005524), microtubule binding (GO:0008017), microtubule severing ATPase activity (GO:0008568), ATP hydrolysis activity (GO:0016887), alpha-tubulin binding (GO:0043014), protein-containing complex binding (GO:0044877), beta-tubulin binding (GO:0048487), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (24): spindle pole (GO:0000922), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endosome (GO:0005768), endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), centrosome (GO:0005813), spindle (GO:0005819), cytosol (GO:0005829), microtubule (GO:0005874), axon (GO:0030424), midbody (GO:0030496), cytoplasmic vesicle (GO:0031410), nuclear membrane (GO:0031965), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), endoplasmic reticulum tubular network (GO:0071782), axon cytoplasm (GO:1904115), endoplasmic reticulum (GO:0005783), cytoskeleton (GO:0005856), microtubule cytoskeleton (GO:0015630), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Nuclear Envelope (NE) Reassembly	1
M Phase	1
Mitotic Anaphase	1
Mitotic Metaphase and Anaphase	1
Cell Cycle, Mitotic	1
Cell Cycle	1

GO top-level categories

showing 60 of 72 GO namespaces:

Category	Terms
cellular anatomical structure	6
cytoplasm	5
mitotic cell cycle	3
microtubule cytoskeleton organization	3
cytokinesis	3
tubulin binding	3
axonal transport	2
axon cytoplasm	2
protein complex oligomerization	2
ATP-dependent activity	2
binding	2
intracellular membrane-bounded organelle	2
endomembrane system	2
organelle membrane	2
endoplasmic reticulum subcompartment	2
intracellular membraneless organelle	2
microtubule cytoskeleton	2
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
intracellular transport	1
Golgi vesicle transport	1
nuclear membrane reassembly	1
mitotic nuclear membrane organization	1
mitotic cell cycle phase transition	1
mitotic nuclear division	1
mitochondrion transport along microtubule	1
axonogenesis	1
central nervous system neuron development	1
microtubule depolymerization	1
positive regulation of microtubule polymerization or depolymerization	1
regulation of microtubule depolymerization	1
positive regulation of protein depolymerization	1
positive regulation of supramolecular fiber organization	1
membrane assembly	1
nuclear membrane organization	1
regulation of cytokinesis	1
positive regulation of cell division	1
positive regulation of cell cycle process	1
cell cycle process	1
mitotic spindle organization	1
spindle disassembly	1
membrane organization	1
cytoskeleton organization	1
microtubule-based process	1
system development	1
animal gross anatomical part developmental process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
polypeptide conformation or assembly isomerase activity	1
catalytic activity, acting on a protein	1
microtubule destabilizing activity	1
ribonucleoside triphosphate phosphatase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
catalytic activity	1
spindle	1
nuclear lumen	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 29 of 58 annotations. The rest are phylogenetic / computational / electronic (IEA).

29 experimentally-supported GO terms:

GO term	NS	Evidence
cytokinetic process	BP	mutant phenotype
endoplasmic reticulum to Golgi vesicle-mediated transport	BP	mutant phenotype
exit from mitosis	BP	mutant phenotype
membrane fission	BP	mutant phenotype
microtubule bundle formation	BP	direct assay
microtubule severing	BP	direct assay
mitotic cytokinesis	BP	mutant phenotype
mitotic spindle disassembly	BP	mutant phenotype
nuclear membrane reassembly	BP	mutant phenotype
positive regulation of cytokinesis	BP	mutant phenotype
protein hexamerization	BP	direct assay
protein homooligomerization	BP	direct assay
axon	CC	direct assay
centrosome	CC	direct assay
cytoplasm	CC	direct assay
cytoplasmic vesicle	CC	direct assay
cytosol	CC	direct assay
endoplasmic reticulum tubular network	CC	direct assay
extracellular exosome	CC	high-throughput assay
midbody	CC	direct assay
nuclear membrane	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
perinuclear region of cytoplasm	CC	direct assay
spindle pole	CC	direct assay
alpha-tubulin binding	MF	physical interaction
beta-tubulin binding	MF	direct assay
microtubule binding	MF	direct assay
microtubule severing ATPase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,156 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPAST	ATL1	Q8WXF7	975
SPAST	REEP1	Q9H902	957
SPAST	ATL2	Q8NHH9	934
SPAST	ATL3	Q6DD88	933
SPAST	SPG11	Q96JI7	929
SPAST	NIPA1	Q7RTP0	929
SPAST	ZFYVE27	Q5T4F4	918
SPAST	CHMP1B	Q7LBR1	905
SPAST	WASHC5	Q12768	875
SPAST	SSNA1	O43805	872
SPAST	RTN1	Q16799	808
SPAST	KIF5A	Q12840	806
SPAST	IST1	P53990	791
SPAST	ZFYVE26	Q68DK2	767
SPAST	ALDH18A1	P54886	762

IntAct

Human interaction partners of SPAST in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

14 partners by confidence:

Partner	Interaction type	MIscore	Records
ATL1	physical association	0.590	5
FBXL17	direct interaction	0.590	2
ZFYVE27	physical association	0.460	3
DCAF8	direct interaction	0.440	1
USP20	direct interaction	0.440	1
SVIL	physical association	0.400	1
ZNF30	physical association	0.400	1
CBLIF	association	0.350	1
PLXNB2	association	0.350	1
RPSA2	association	0.350	1
SKP1	association	0.350	1
AURKB	colocalization	0.270	1
GAS2L3	colocalization	0.270	1
REEP5	colocalization	0.270	1

BioGRID (111 interactions; top human partners by supporting records): IST1 (Affinity Capture-MS; 5 records), FBXL17 (Reconstituted Complex; 3 records), NUP107 (Affinity Capture-MS; 3 records), NUP133 (Affinity Capture-MS; 3 records), NUP43 (Affinity Capture-MS; 3 records), NUP85 (Affinity Capture-MS; 3 records), NUP98 (Affinity Capture-MS; 3 records), CHMP1B (Two-hybrid; 2 records), NUP160 (Affinity Capture-MS; 2 records), WDR45 (Affinity Capture-MS; 2 records), ALB (Affinity Capture-MS), CAPZB (Affinity Capture-MS), CEBPA (Protein-peptide), CHMP2A (Affinity Capture-MS), CHMP4B (Affinity Capture-MS)

SIGNOR signaling

5 signaling interactions:

A	Effect	B	Mechanism
NRF1	“up-regulates quantity by expression”	SPAST	“transcriptional regulation”
SOX11	“up-regulates quantity by expression”	SPAST	“transcriptional regulation”
IST1	“up-regulates activity”	SPAST	relocalization
SPAST	up-regulates	Neurite_outgrowth
SPAST	up-regulates	Microtubule_polimerization	cleavage

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
SPG3A-SPG4-SPG31 complex	3	ATL1, REEP1, SPAST
SPAST-ZFYVE27 complex	2	SPAST, ZFYVE27
RNT2-SPAST complex	2	RTN2, SPAST

Disease & clinical

Genetic variants

Variant evidence for SPAST: 1,639 ClinVar records (663 pathogenic / likely pathogenic); 6 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,639 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	510
Likely pathogenic	153
Uncertain significance	472
Likely benign	243
Benign	55

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 663 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
226113	NM_014946.4(SPAST):c.1245+1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	19
240948	NM_014946.4(SPAST):c.1378C>T (p.Arg460Cys)	Pathogenic	criteria provided, multiple submitters, no conflicts	17
188179	NM_014946.4(SPAST):c.1291C>T (p.Arg431Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	14
448449	NM_014946.4(SPAST):c.1684C>T (p.Arg562Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
5675	NM_014946.4(SPAST):c.1216A>G (p.Ile406Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
988982	NM_014946.4(SPAST):c.1741C>T (p.Arg581Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
805511	NM_014946.4(SPAST):c.1413+1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	7
5664	NM_014946.4(SPAST):c.1322A>G (p.Asp441Gly)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
931483	NM_014946.4(SPAST):c.870+1G>T	Pathogenic	criteria provided, multiple submitters, no conflicts	6
5661	NM_014946.4(SPAST):c.1688-2A>G	Pathogenic	criteria provided, multiple submitters, no conflicts	5
208644	NM_014946.4(SPAST):c.1168A>G (p.Met390Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
409031	NM_014946.4(SPAST):c.1276C>G (p.Leu426Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
448456	NM_014946.4(SPAST):c.838C>T (p.Gln280Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
468562	NM_014946.4(SPAST):c.1215_1219del (p.Asn405fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
523507	NM_014946.4(SPAST):c.1039C>T (p.Gln347Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5

Per-variant reference — Sugi Variant

Explore SPAST’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 25 predictions of 1,190):

Position(s)	Effect	Δscore	Sites
2:32064247–32064248	donor_loss	1.0000	3
2:32087579–32087580	donor_loss	1.0000	5
2:32089520–32089521	acceptor_loss	1.0000	5
2:32098770	acceptor_gain	1.0000
2:32098779	acceptor_gain	1.0000
2:32098786	acceptor_gain	1.0000
2:32098789	acceptor_gain	1.0000
2:32098793	acceptor_gain	1.0000
2:32115700–32115701	acceptor_gain	1.0000	2
2:32115836–32115837	donor_loss	1.0000	5

AlphaMissense

1,613 missense substitutions predicted likely pathogenic (of 3,992 scored), across 358 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M181	9	0.981	0.999
M187	9	0.898	0.990
D441	8	0.999	0.999
D444	8	0.999	1.000
D493	8	0.998	0.999
D584	8	0.998	0.999
D548	8	0.997	0.999
F368	8	0.995	1.000
F439	8	0.995	1.000
F427	8	0.994	0.999
D555	8	0.991	0.999
F585	8	0.988	1.000
N487	8	0.986	1.000
F403	8	0.983	0.999
D134	8	0.977	0.993
D470	8	0.976	0.996
H120	8	0.974	0.999
F381	8	0.971	0.999
F465	8	0.971	0.999
F124	8	0.967	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.00031
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000371

Disease associations

OMIM: gene MIM:604277 | disease phenotypes: MIM:182601, MIM:303350, MIM:312920

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
hereditary spastic paraplegia 4	Definitive	Autosomal dominant	7
SPAST-related motor disorder	Strong	Autosomal recessive
neurodevelopmental disorder	Strong	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (13 panels, 13 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

13 panels:

Panel	Rating
Adult-onset neurological disorders	green
Amyotrophic lateral sclerosis/motor neuron disease	green
DDG2P	green
Hereditary neuropathy	green
Hereditary neuropathy or pain disorder	green
Hereditary spastic paraplegia	green
Hereditary spastic paraplegia, adult onset	green
Hereditary spastic paraplegia, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Neurodegenerative disorders, adult onset	green
Paediatric disorders	green

Mondo (7): hereditary spastic paraplegia 4 (MONDO:0008438), hereditary spastic paraplegia (MONDO:0019064), cerebral palsy (MONDO:0006497), hereditary spastic paraplegia 2 (MONDO:0010733), tic disorder (MONDO:0002420), SPAST-related motor disorder (MONDO:0100523), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Autosomal dominant spastic paraplegia type 4 (Orphanet:100985), Hereditary spastic paraplegia (Orphanet:685), Spastic paraplegia type 2 (Orphanet:99015)

HPO phenotypes

40 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0000639	Nystagmus
HP:0000713	Agitation
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000726	Dementia
HP:0000734	Disinhibition
HP:0000741	Apathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001761	Pes cavus
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002314	Degeneration of the lateral corticospinal tracts
HP:0002354	Memory impairment
HP:0002839	Urinary bladder sphincter dysfunction
HP:0003419	Low back pain
HP:0003487	Babinski sign
HP:0003587	Insidious onset
HP:0003676	Progressive
HP:0003693	Distal amyotrophy
HP:0003743	Genetic anticipation
HP:0003828	Variable expressivity
HP:0004302	Functional motor deficit
HP:0006938	Impaired vibration sensation at ankles
HP:0007340	Lower limb muscle weakness
HP:0007350	Upper limb hyperreflexia
HP:0008969	Leg muscle stiffness
HP:0010550	Paraplegia
HP:0011448	Ankle clonus
HP:0100543	Cognitive impairment

GWAS associations

6 associations:

Study	Trait	p-value
GCST006661_152	Male-pattern baldness	7e-26
GCST006661_129	Male-pattern baldness	4e-20
GCST002255_2	Inflammatory biomarkers	3e-19
GCST009736_2	Interleukin-18 levels	3e-19
GCST010241_374	Apolipoprotein A1 levels	1e-10
GCST008097_14	Bisphosphonate-associated atypical femoral fracture	8e-7

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0004812	interleukin-1 beta measurement
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture
EFO:0004581	interleukin 18 measurement
EFO:0004614	apolipoprotein A 1 measurement

MeSH disease descriptors

5 disease descriptors:

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D065886	Neurodevelopmental Disorders	F03.625
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
D013981	Tic Disorders	C10.228.662.825; F03.625.992
C536865	Spastic paraplegia 4, autosomal dominant *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169203 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

2 measured of 2 human assays (2 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5190401	IC50	99 nM
CHEMBL5201542	IC50	4400 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.00	IC50	99	nM	CHEMBL5190401
5.36	IC50	4400	nM	CHEMBL5201542

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(5-tert-butyl-1H-pyrazol-3-yl)-2-[(3R)-3-propan-2-ylpiperazin-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine	1846614: Inhibition of human Spastin in presence of ATP	ic50	0.0990	uM
N-(5-tert-butyl-1H-pyrazol-3-yl)-2-[(2R)-2-methylpiperazin-1-yl]quinazolin-4-amine	1846614: Inhibition of human Spastin in presence of ATP	ic50	4.4000	uM

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
trichostatin A	affects cotreatment, decreases expression	3
Particulate Matter	decreases reaction, increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
beta-lapachone	decreases expression	1
arsenite	decreases reaction, affects binding	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
triacsin C	decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Vehicle Emissions	decreases reaction, increases expression	1
Caffeine	affects phosphorylation	1
Doxorubicin	decreases expression	1
Gold	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Nickel	decreases expression	1
Phthalic Acids	increases methylation	1
Quercetin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5097625	Binding	Inhibition of human Spastin in presence of ATP	AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors. — *Eur J Med Chem*

Cellosaurus cell lines

10 cell lines: 5 induced pluripotent stem cell, 2 transformed cell line, 2 finite cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3I0	Abcam HEK293T SPAST KO	Transformed cell line	Female
CVCL_B7BR	HIHCNi006-A-1	Induced pluripotent stem cell	Male
CVCL_B7BS	HIHCNi006-A-2	Induced pluripotent stem cell	Male
CVCL_C3RJ	HIHCNi008-A-1	Induced pluripotent stem cell	Male
CVCL_C3RK	HIHCNi008-A-2	Induced pluripotent stem cell	Male
CVCL_D2ZY	GM28977	Finite cell line	Male
CVCL_D9SU	Ubigene HEK293 SPAST KO	Transformed cell line	Female
CVCL_E2KP	HAP1 SPAST (-)	Cancer cell line	Male
CVCL_F0Z3	GM29367	Finite cell line	Male
CVCL_IJ21	iPS-SPG4-splice	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 508 trials:

NCT	Phase	Status	Title
NCT04586348	Phase 4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	Phase 4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT07542548	Phase 4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT07803276	Phase 4	RECRUITING	Comparison Between Palpatory and Ultrasound-guided Methods for Botulinum Toxin Administration in Spastic Paraplegia
NCT00154830	Phase 4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	Phase 4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	Phase 4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	Phase 4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	Phase 4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	Phase 4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	Phase 4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	Phase 4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	Phase 4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	Phase 4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	Phase 4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	Phase 4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	Phase 4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	Phase 4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	Phase 4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	Phase 4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT02559102	Phase 3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	Phase 3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	Phase 3	RECRUITING	Reducing Missed Appointments
NCT07377032	Phase 3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00014989	Phase 3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	Phase 3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	Phase 3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	Phase 3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	Phase 3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	Phase 3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	Phase 3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	Phase 3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	Phase 3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	Phase 3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	Phase 3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	Phase 3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	Phase 3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	Phase 3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	Phase 3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	Phase 3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01898520	Phase 3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	Phase 3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	Phase 3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy
NCT02270736	Phase 3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02839785	Phase 3	TERMINATED	Analgesia and Physiotherapy in Children With Cerebral Palsy (ANTALKINECP)
NCT03110341	Phase 3	UNKNOWN	Effect of Erythropoietin in Premature Infants on White Matter Lesions and Neurodevelopmental Outcome
NCT03302871	Phase 3	COMPLETED	Integrated Management Enhances Functional Gains in Children With Cerebral Palsy Treated by BoNT-A
NCT03306212	Phase 3	COMPLETED	Efficacy of Intermittent Serial Casting on Spastic Wrist Flexion Deformity
NCT03469999	Phase 3	COMPLETED	Effect of Dysport Injections on Energy Expenditure and Walking Efficiency in Children With Cerebral Palsy
NCT03472261	Phase 3	COMPLETED	Integrated Management of Pronation Deformity in Cerebral Palsy
NCT03616067	Phase 3	TERMINATED	Evaluation of the Efficacy of the Injection of Botulinum Toxin A vs Scopolamine Patches in the Treatment of Drooling in Children With Cerebral Palsy
NCT05206513	Phase 3	COMPLETED	Study to Assess the Efficacy, Safety, and Tolerability of Valbenazine for the Treatment of Dyskinesia Due to Cerebral Palsy
NCT06128616	Phase 3	UNKNOWN	Efficacy of Extracorporeal Shock Wave Therapy in Children With Cerebral Palsy
NCT06840158	Phase 3	COMPLETED	Double-blind Comparative Randomized Multicenter
NCT07524972	Phase 3	RECRUITING	Antenatal Magnesium Sulphate in High-Risk Preterm Patients
NCT07672158	Phase 3	NOT_YET_RECRUITING	Tranexamic Acid to Reduce Blood Loss After Varus Derotation Osteotomy
NCT02909959	Phase 2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	Phase 2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	Phase 2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT03961906	Phase 2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for SPAST across ~30M SureChEMBL compounds — explore on Sugi Predict.