AP5Z1

Summary

AP5Z1 (adaptor related protein complex 5 subunit zeta 1, HGNC:22197) is a protein-coding gene on chromosome 7p22.1, encoding AP-5 complex subunit zeta-1 (O43299). As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.

This gene was identified by genome-wide screen for genes involved in homologous recombination DNA double-strand break repair (HR-DSBR). The encoded protein was found in a complex with other proteins that have a role in HR-DSBR. Knockdown of this gene reduced homologous recombination, and mutations in this gene were found in patients with spastic paraplegia. It was concluded that this gene likely encodes a helicase (PMID:20613862).

Source: NCBI Gene 9907 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,269 total — 27 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• MANE Select transcript: NM_014855

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22197
Approved symbol	AP5Z1
Name	adaptor related protein complex 5 subunit zeta 1
Location	7p22.1
Locus type	gene with protein product
Status	Approved
Aliases	SPG48, zeta
Ensembl gene	ENSG00000242802
Ensembl biotype	protein_coding
OMIM	613653
Entrez	9907

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 16 protein_coding, 9 retained_intron, 6 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000469614, ENST00000477454, ENST00000477680, ENST00000490487, ENST00000491375, ENST00000496303, ENST00000647628, ENST00000647984, ENST00000648237, ENST00000648360, ENST00000648765, ENST00000648925, ENST00000649063, ENST00000649315, ENST00000649419, ENST00000649736, ENST00000650310, ENST00000650451, ENST00000650581, ENST00000865634, ENST00000865635, ENST00000865636, ENST00000865637, ENST00000913390, ENST00000963389, ENST00000963390, ENST00000963391, ENST00000963392, ENST00000963393, ENST00000963394, ENST00000963395, ENST00000963396

RefSeq mRNA: 2 — MANE Select: NM_014855 NM_001364858, NM_014855

CCDS: CCDS47528

Canonical transcript exons

ENST00000649063 — 17 exons

Exon	Start	End
ENSE00003462658	4785522	4785684
ENSE00003480743	4789832	4789929
ENSE00003486268	4781568	4781754
ENSE00003488272	4790459	4790591
ENSE00003494270	4788154	4788294
ENSE00003522959	4784908	4785048
ENSE00003573021	4783689	4783798
ENSE00003583444	4790673	4790887
ENSE00003606863	4786250	4786428
ENSE00003612596	4788840	4788951
ENSE00003643676	4781175	4781312
ENSE00003653180	4787634	4787776
ENSE00003656668	4783316	4783460
ENSE00003670760	4784203	4784371
ENSE00003678027	4785415	4785452
ENSE00003838919	4775623	4775756
ENSE00003840628	4791115	4794397

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 95.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.6906 / max 327.2458, expressed in 1817 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77078	26.6906	1817

Top tissues by expression

271 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	95.06	gold quality
tendon of biceps brachii	UBERON:0008188	94.64	gold quality
buccal mucosa cell	CL:0002336	93.43	silver quality
skin of leg	UBERON:0001511	92.38	gold quality
right adrenal gland cortex	UBERON:0035827	92.28	gold quality
right adrenal gland	UBERON:0001233	92.01	gold quality
mucosa of transverse colon	UBERON:0004991	91.97	gold quality
spleen	UBERON:0002106	91.91	gold quality
left adrenal gland	UBERON:0001234	91.84	gold quality
left adrenal gland cortex	UBERON:0035825	91.67	gold quality
sural nerve	UBERON:0015488	91.41	gold quality
skin of abdomen	UBERON:0001416	91.20	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.89	gold quality
lower esophagus mucosa	UBERON:0035834	90.55	gold quality
adrenal cortex	UBERON:0001235	90.43	gold quality
body of stomach	UBERON:0001161	90.24	gold quality
adenohypophysis	UBERON:0002196	90.18	gold quality
metanephros cortex	UBERON:0010533	90.06	gold quality
transverse colon	UBERON:0001157	89.86	gold quality
mucosa of stomach	UBERON:0001199	89.84	gold quality
blood	UBERON:0000178	89.61	gold quality
upper lobe of left lung	UBERON:0008952	89.48	gold quality
stromal cell of endometrium	CL:0002255	89.37	gold quality
adrenal gland	UBERON:0002369	89.31	gold quality
apex of heart	UBERON:0002098	89.27	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.14	gold quality
right lobe of thyroid gland	UBERON:0001119	89.11	gold quality
lower esophagus	UBERON:0013473	89.11	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.11	gold quality
muscle layer of sigmoid colon	UBERON:0035805	88.92	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.17

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• Here, we have generated induced pluripotent stem cells (iPSCs) from patients with two autosomal recessive forms of hereditary spastic paraplegia (HSP) , SPG15 and SPG48, which are caused by mutations in the ZFYVE26 and AP5Z1 genes encoding proteins in the same complex, the spastizin and AP5Z1 proteins, respectively. (PMID:29726929)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap5z1	ENSDARG00000078111
mus_musculus	Ap5z1	ENSMUSG00000039623
rattus_norvegicus	AABR07035428.2	ENSRNOG00000056768
drosophila_melanogaster	Lpin	FBGN0263593
caenorhabditis_elegans		WBGENE00010425

Paralogs (3): LPIN2 (ENSG00000101577), LPIN3 (ENSG00000132793), LPIN1 (ENSG00000134324)

Protein

Protein identifiers

AP-5 complex subunit zeta-1 — O43299 (reviewed: O43299)

Alternative names: Adaptor-related protein complex 5 zeta subunit

All UniProt accessions (8): A0A3B3IRY2, A0A3B3IRY4, A0A3B3IS81, A0A3B3ISJ0, A0A3B3ISN8, A0A3B3ITJ1, A0A3B3IU94, O43299

UniProt curated annotations — full annotation on UniProt →

Function. As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport. According to PubMed:20613862 it is a putative helicase required for efficient homologous recombination DNA double-strand break repair.

Subunit / interactions. Probably part of the adaptor protein complex 5 (AP-5) a tetramer composed of AP5B1, AP5M1, AP5S1 and AP5Z1. Interacts with ZFYVE26 and SPG11.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Spastic paraplegia 48, autosomal recessive (SPG48) [MIM:613647] 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.

Isoforms (3)

UniProt ID	Names	Canonical?
O43299-1	1	yes
O43299-2	2
O43299-3	3

RefSeq proteins (2): NP_001351787, NP_055670* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR028222	AP5Z1	Family
IPR055450	AP5Z1_ARM	Domain
IPR056856	TPR_AP5Z1_C	Domain
IPR056857	TPR_AP5Z1_N	Domain

Pfam: PF14764, PF25153, PF25154

UniProt features (7 total): splice variant 5, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43299-F1	85.32	0.56

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 186 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, chr7p22, GOBP_MACROAUTOPHAGY, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_DNA_DAMAGE_RESPONSE, GOBP_ORGANELLE_ASSEMBLY, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, GOBP_LYTIC_VACUOLE_ORGANIZATION, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (15): autophagosome assembly (GO:0000045), double-strand break repair via homologous recombination (GO:0000724), intracellular protein transport (GO:0006886), Golgi organization (GO:0007030), lysosome organization (GO:0007040), gene expression (GO:0010467), vesicle-mediated transport (GO:0016192), endosomal transport (GO:0016197), late endosome to Golgi transport (GO:0034499), axon development (GO:0061564), lysosomal protein catabolic process (GO:1905146), DNA repair (GO:0006281), autophagy (GO:0006914), DNA damage response (GO:0006974), protein transport (GO:0015031)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), lysosome (GO:0005764), late endosome (GO:0005770), nuclear speck (GO:0016607), AP-type membrane coat adaptor complex (GO:0030119), AP-5 adaptor complex (GO:0044599)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular protein localization	2
intracellular transport	2
transport	2
cellular anatomical structure	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
recombinational repair	1
double-strand break repair	1
protein transport	1
organelle organization	1
endomembrane system organization	1
lytic vacuole organization	1
macromolecule biosynthetic process	1
cellular process	1
vesicle-mediated transport	1
cytoplasm	1
retrograde transport, endosome to Golgi	1
Golgi vesicle transport	1
neuron projection development	1
lysosome	1
protein catabolic process in the vacuole	1
DNA metabolic process	1
DNA damage response	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
cellular response to stress	1
establishment of protein localization	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
lytic vacuole	1
endosome	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

928 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP5Z1	SPG11	Q96JI7	994
AP5Z1	ZFYVE26	Q68DK2	992
AP5Z1	AP5B1	Q2VPB7	980
AP5Z1	AP5S1	Q9NUS5	972
AP5Z1	PNPLA6	Q8IY17	866
AP5Z1	SPG21	Q9NZD8	864
AP5Z1	GJC2	Q5T442	839
AP5Z1	SPG7	Q9UQ90	820
AP5Z1	SPART	Q8N0X7	775
AP5Z1	AP5M1	Q9H0R1	742
AP5Z1	TECPR2	O15040	720
AP5Z1	MTRFR	Q9H3J6	688
AP5Z1	CYP2U1	Q7Z449	680
AP5Z1	AP4S1	Q9Y587	677
AP5Z1	B4GALNT1	Q00973	661

IntAct

36 interactions, top by confidence:

A	B	Type	Score
SPG11	AP5Z1	psi-mi:“MI:0914”(association)	0.620
SPG11	AP5Z1	psi-mi:“MI:0915”(physical association)	0.620
AP5Z1	NUP93	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE26	AP5Z1	psi-mi:“MI:0914”(association)	0.540
ZFYVE26	AP5Z1	psi-mi:“MI:0915”(physical association)	0.540
AP5Z1	ZFYVE26	psi-mi:“MI:0403”(colocalization)	0.540
AP5Z1	ZFYVE26	psi-mi:“MI:0915”(physical association)	0.540
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
AP5S1	AP5Z1	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
AP5Z1	Dctn1	psi-mi:“MI:0915”(physical association)	0.400
YWHAB	AP5Z1	psi-mi:“MI:0915”(physical association)	0.400
MDFI	AP5Z1	psi-mi:“MI:0915”(physical association)	0.370
FOXK1	AP5Z1	psi-mi:“MI:0914”(association)	0.350
FOXK1	PHKG2	psi-mi:“MI:0914”(association)	0.350
BUB1B	AP5Z1	psi-mi:“MI:0914”(association)	0.350
PTH2R	METTL15	psi-mi:“MI:0914”(association)	0.350
SAYSD1	CCDC85C	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
FPR1	GPR89A	psi-mi:“MI:0914”(association)	0.350
LYPD4	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
AP5S1	NHERF1	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
BAG2	PIK3C2A	psi-mi:“MI:0914”(association)	0.350
AP5Z1	TUSC2	psi-mi:“MI:0914”(association)	0.350
IRF2	AP5Z1	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): AP5Z1 (Two-hybrid), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), AP5Z1 (Two-hybrid), AP5Z1 (Proximity Label-MS), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-RNA), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS), AP5Z1 (Affinity Capture-MS)

ESM2 similar proteins: A0JN53, A1L3T7, C9JE40, D2I4M3, G3HQ82, O43299, O75800, O94812, P58660, Q0P5G1, Q15572, Q1RMI8, Q1W1Y5, Q3T1I9, Q3U829, Q56B11, Q571B6, Q58CQ5, Q5ND34, Q5R8S0, Q66H85, Q6NZL6, Q6ZNJ1, Q6ZQA0, Q76MJ5, Q80TE0, Q80UU1, Q80UW5, Q8BGI5, Q8BMG1, Q8C3R1, Q8C3S2, Q8C7B8, Q8CE13, Q8IZL8, Q8N163, Q8VDP4, Q8WXE1, Q96HA7, Q9BQG0

Diamond homologs: O43299, Q3U829

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AP5Z1	“form complex”	“AP-5 Adaptor complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1269 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	34
Uncertain significance	606
Likely benign	350
Benign	94

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1033302	NM_014855.3(AP5Z1):c.158C>A (p.Ser53Ter)	Pathogenic
1323294	NM_014855.3(AP5Z1):c.1323G>A (p.Trp441Ter)	Pathogenic
1366715	NM_014855.3(AP5Z1):c.2079_2100del (p.Cys693_Pro694insTer)	Pathogenic
1458218	NM_014855.3(AP5Z1):c.49C>T (p.Gln17Ter)	Pathogenic
2007501	NM_014855.3(AP5Z1):c.896_902dup (p.Cys301Ter)	Pathogenic
2041213	NM_014855.3(AP5Z1):c.2079_2091del (p.Cys693fs)	Pathogenic
2151423	NM_014855.3(AP5Z1):c.67A>T (p.Lys23Ter)	Pathogenic
2853047	NM_014855.3(AP5Z1):c.704del (p.Asp235fs)	Pathogenic
2862357	NM_014855.3(AP5Z1):c.1954G>T (p.Glu652Ter)	Pathogenic
2997932	NM_014855.3(AP5Z1):c.2079del (p.Gln696fs)	Pathogenic
3	NM_014855.3(AP5Z1):c.1413_1426del (p.Leu473fs)	Pathogenic
3249399	NM_014855.3(AP5Z1):c.2336_2339dup (p.His780fs)	Pathogenic
3653876	NM_014855.3(AP5Z1):c.670dup (p.Thr224fs)	Pathogenic
3685198	NM_014855.3(AP5Z1):c.1042_1043del (p.Ser348fs)	Pathogenic
3716976	NM_014855.3(AP5Z1):c.1499_1500del (p.Leu500fs)	Pathogenic
375313	NM_014855.3(AP5Z1):c.1322G>A (p.Trp441Ter)	Pathogenic
375316	NM_014855.3(AP5Z1):c.1732C>T (p.Gln578Ter)	Pathogenic
4723357	NM_014855.3(AP5Z1):c.1308dup (p.Lys437Ter)	Pathogenic
4738340	NM_014855.3(AP5Z1):c.2086del (p.Gln696fs)	Pathogenic
4777569	NM_014855.3(AP5Z1):c.1068_1098del (p.Val357fs)	Pathogenic
567257	NM_014855.3(AP5Z1):c.210_231del (p.Gln70fs)	Pathogenic
578441	NM_014855.3(AP5Z1):c.706C>T (p.Gln236Ter)	Pathogenic
590776	NM_014855.3(AP5Z1):c.1343_1346dup (p.Glu449fs)	Pathogenic
989046	NM_014855.3(AP5Z1):c.1323del (p.Ala440_Trp441insTer)	Pathogenic
989047	NM_014855.3(AP5Z1):c.1596-3C>G	Pathogenic
989048	NM_014855.3(AP5Z1):c.1730_1733del (p.Asn577fs)	Pathogenic
989049	NM_014855.3(AP5Z1):c.1939-1G>A	Pathogenic
1030377	NM_014855.3(AP5Z1):c.179+1G>T	Likely pathogenic
1067378	NC_000007.13:g.(?_4816199)_4825153del	Likely pathogenic
1344214	NM_014855.3(AP5Z1):c.1543C>T (p.Gln515Ter)	Likely pathogenic

SpliceAI

3043 predictions. Top by Δscore:

Variant	Effect	Δscore
7:4781173:A:AG	acceptor_gain	1.0000
7:4781173:AG:A	acceptor_gain	1.0000
7:4781173:AGG:A	acceptor_gain	1.0000
7:4781174:G:A	acceptor_gain	1.0000
7:4781174:G:GG	acceptor_gain	1.0000
7:4781174:G:GT	acceptor_loss	1.0000
7:4781174:GGG:G	acceptor_gain	1.0000
7:4781174:GGGA:G	acceptor_gain	1.0000
7:4781298:G:GT	donor_gain	1.0000
7:4781309:GGAG:G	donor_gain	1.0000
7:4781310:GAG:G	donor_gain	1.0000
7:4781310:GAGG:G	donor_gain	1.0000
7:4781311:AGGTG:A	donor_loss	1.0000
7:4781312:GGTG:G	donor_loss	1.0000
7:4781313:G:GG	donor_gain	1.0000
7:4781313:G:T	donor_loss	1.0000
7:4781314:T:G	donor_loss	1.0000
7:4784201:A:AG	acceptor_gain	1.0000
7:4784201:AGCC:A	acceptor_gain	1.0000
7:4784201:AGCCG:A	acceptor_gain	1.0000
7:4784202:G:GG	acceptor_gain	1.0000
7:4784202:GC:G	acceptor_gain	1.0000
7:4784202:GCC:G	acceptor_gain	1.0000
7:4784202:GCCG:G	acceptor_gain	1.0000
7:4784202:GCCGG:G	acceptor_gain	1.0000
7:4785040:G:GG	donor_gain	1.0000
7:4785046:GAC:G	donor_gain	1.0000
7:4785049:G:GG	donor_gain	1.0000
7:4785049:GTGA:G	donor_loss	1.0000
7:4785684:GGTG:G	donor_loss	1.0000

AlphaMissense

5171 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:4785534:G:C	A328P	0.995
7:4784252:C:A	T224K	0.994
7:4785028:T:C	L304P	0.994
7:4784308:T:C	F243L	0.993
7:4784310:C:A	F243L	0.993
7:4784310:C:G	F243L	0.993
7:4785015:T:C	Y300H	0.992
7:4785025:G:C	R303P	0.992
7:4790860:C:A	A709D	0.992
7:4784298:C:A	N239K	0.991
7:4784298:C:G	N239K	0.991
7:4785020:C:G	C301W	0.991
7:4783728:T:C	L184P	0.990
7:4785522:T:C	C324R	0.990
7:4784248:T:C	F223L	0.989
7:4784250:C:A	F223L	0.989
7:4784250:C:G	F223L	0.989
7:4784309:T:C	F243S	0.989
7:4785015:T:G	Y300D	0.989
7:4787740:T:C	L473P	0.989
7:4791222:T:C	L754P	0.989
7:4784252:C:G	T224R	0.988
7:4785018:T:C	C301R	0.988
7:4785016:A:G	Y300C	0.987
7:4785524:C:G	C324W	0.987
7:4787641:C:A	A440D	0.987
7:4787643:T:A	W441R	0.987
7:4787643:T:C	W441R	0.987
7:4790868:A:C	S712R	0.987
7:4790870:C:A	S712R	0.987

dbSNP variants (sampled 300 via entrez): RS1000010140 (7:4780727 CTA>C), RS1000029991 (7:4783736 G>A,T), RS1000124036 (7:4787906 C>A,G,T), RS1000166805 (7:4783592 A>G), RS1000242000 (7:4777733 G>A), RS1000279157 (7:4786264 G>A), RS1000364205 (7:4789023 G>C,T), RS1000379643 (7:4786563 G>A,T), RS1000423389 (7:4793657 G>A), RS1000429315 (7:4788682 G>A,T), RS1000589136 (7:4783733 T>C), RS1000712953 (7:4785512 T>A,C), RS1000776196 (7:4786162 G>A), RS1000843870 (7:4776777 A>G), RS1000978059 (7:4790507 G>C)

Disease associations

OMIM: gene MIM:613653 | disease phenotypes: MIM:613647, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 48	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary spastic paraplegia	Definitive	AR

Mondo (5): hereditary spastic paraplegia 48 (MONDO:0013342), inherited retinal dystrophy (MONDO:0019118), hereditary spastic paraplegia (MONDO:0019064), optic atrophy (MONDO:0003608), megacolon (MONDO:0001273)

Orphanet (3): Autosomal recessive spastic paraplegia type 48 (Orphanet:306511), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000488	Retinopathy
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001268	Mental deterioration
HP:0001300	Parkinsonism
HP:0001310	Dysmetria
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002079	Hypoplasia of the corpus callosum
HP:0002136	Broad-based gait
HP:0002313	Spastic paraparesis
HP:0002839	Urinary bladder sphincter dysfunction
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003319	Abnormality of the cervical spine
HP:0003593	Infantile onset
HP:0003596	Middle age onset
HP:0003676	Progressive
HP:0007020	Progressive spastic paraplegia
HP:0007340	Lower limb muscle weakness
HP:0009830	Peripheral neuropathy
HP:0030051	Tip-toe gait
HP:0030890	Hyperintensity of cerebral white matter on MRI
HP:0030891	Periventricular white matter hyperintensities

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003395_42	Parental extreme longevity (95 years and older)	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007796	parental longevity

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008531	Megacolon	C06.405.469.158.701
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724750 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
Cyclosporine	increases expression	3
sodium arsenite	increases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
Air Pollutants	increases abundance, affects cotreatment, affects expression	2
Ozone	increases abundance, affects cotreatment, affects expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
bisphenol A	decreases expression	1
geraniol	increases expression	1
perfluorooctanoic acid	decreases expression	1
methacrylaldehyde	affects cotreatment, affects expression, increases abundance	1
perfluoro-n-nonanoic acid	decreases expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
licochalcone B	increases expression	1
NSC 689534	affects binding, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Acrolein	increases abundance, affects cotreatment, affects expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases mutagenesis	1
Copper	affects binding, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Ivermectin	decreases expression	1
Silver	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697490	Binding	Inhibition of KIAA0415 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SC85	HAP1 AP5Z1 (-) 1	Cancer cell line	Male
CVCL_SC86	HAP1 AP5Z1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

100 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
NCT05820100	Not specified	COMPLETED	Observational Study to Assess the Reliability and Validity of the MLYMT and MLSDT
NCT05976139	Not specified	RECRUITING	Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies
NCT06162585	Not specified	ACTIVE_NOT_RECRUITING	Non-Interventional Long Term Follow-up Study of Participants Previously Enrolled in the RESTORE Study
NCT06177977	Not specified	RECRUITING	SS-HH-OCT as a Novel Diagnostic Modality for Early-Onset Retinal Dystrophies (EORDs)