AP4M1

Summary

AP4M1 (adaptor related protein complex 4 subunit mu 1, HGNC:574) is a protein-coding gene on chromosome 7q22.1, encoding AP-4 complex subunit mu-1 (O00189). Component of the adaptor protein complex 4 (AP-4).

This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system.

Source: NCBI Gene 9179 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AP-4 deficiency syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 612 total — 33 pathogenic, 28 likely-pathogenic (top 5% of genes corpus-wide)
• GTEx eGene: eQTL in 44 tissues, sQTL in 22 (q < 0.05)
• Phenotypes (HPO): 54
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.11 (unconstrained)
• MANE Select transcript: NM_004722
• Interaction hub: 2,152 STRING partners (top 6% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:574
Approved symbol	AP4M1
Name	adaptor related protein complex 4 subunit mu 1
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MU-ARP2, MU-4, SPG50
Ensembl gene	ENSG00000221838
Ensembl biotype	protein_coding
OMIM	602296
Entrez	9179

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 29 protein_coding, 19 nonsense_mediated_decay, 7 retained_intron

MANE Select: ENST00000359593

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 4, TSL 3: 4, TSL 5: 7

ENST00000359593, ENST00000394061, ENST00000416938, ENST00000421755, ENST00000422582, ENST00000429084, ENST00000438383, ENST00000439416, ENST00000445208, ENST00000445295, ENST00000446007, ENST00000450807, ENST00000463195, ENST00000478501, ENST00000479916, ENST00000489387, ENST00000495154, ENST00000713591, ENST00000713791, ENST00000713792, ENST00000713793, ENST00000713794, ENST00000713795, ENST00000713796, ENST00000713797, ENST00000713798, ENST00000713799, ENST00000907395, ENST00000907396, ENST00000907397, ENST00000918985, ENST00000918986, ENST00000918987, ENST00000970612, ENST00000970613, ENST00000970614, ENST00000970615, ENST00000970616, ENST00000970617, ENST00000970618, ENST00001006648, ENST00001006649, ENST00001011100, ENST00001011101, ENST00001011102, ENST00001011103, ENST00001011104, ENST00001011105, ENST00001011106, ENST00001076930, ENST00001117637, ENST00001126259, ENST00001126260, ENST00001126261, ENST00001138186

RefSeq mRNA: 11 — MANE Select: NM_004722 NM_001363671, NM_001438824, NM_001438825, NM_001438826, NM_001438827, NM_001438828, NM_001438829, NM_001438830, NM_001438831, NM_001438832, NM_004722

CCDS: CCDS5685, CCDS87527

Canonical transcript exons

ENST00000359593 — 15 exons

Exon	Start	End
ENSE00000824885	100101880	100101968
ENSE00003460402	100103612	100103692
ENSE00003465877	100105240	100105346
ENSE00003513974	100105959	100106003
ENSE00003514525	100104874	100104940
ENSE00003539558	100103409	100103519
ENSE00003592557	100105045	100105098
ENSE00003611752	100106241	100106291
ENSE00003643570	100102864	100102960
ENSE00003680628	100104092	100104154
ENSE00003681749	100102675	100102781
ENSE00003785646	100105445	100105539
ENSE00003789291	100106403	100106514
ENSE00004021358	100106658	100109039
ENSE00004021371	100101643	100101772

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 94.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3013 / max 54.2730, expressed in 1747 samples.

Highest expression (Bgee): testis, uterine tube, adenohypophysis, cortical plate, stromal cell of endometrium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

AP4M1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 44 tissues and its splicing (sQTL) in 22 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 66 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	6.7e-82	-0.70	7:100116427:G:T
Nerve Tibial	eqtl	1.7e-60	-0.50	7:100102003:T:C
Artery Tibial	eqtl	1.4e-53	-0.46	7:100102003:T:C
Esophagus Muscularis	eqtl	6.5e-53	-0.48	7:100112961:A:AG
Adipose Subcutaneous	eqtl	3.8e-48	-0.41	7:100102003:T:C
Artery Aorta	eqtl	1.1e-41	-0.50	7:100112961:A:AG
Breast Mammary Tissue	eqtl	8.5e-40	-0.39	7:100107173:A:T
Whole Blood	eqtl	3.1e-37	-0.36	7:100102003:T:C
Esophagus Mucosa	eqtl	4.9e-33	-0.44	7:100102003:T:C
Adipose Visceral Omentum	eqtl	5.0e-33	-0.33	7:100102003:T:C
Esophagus Gastroesophageal Junction	eqtl	3.9e-32	-0.46	7:100102003:T:C
Cells EBV-transformed lymphocytes	eqtl	3.3e-31	-0.77	7:100102003:T:C
Thyroid	eqtl	6.8e-28	-0.33	7:100102003:T:C
Colon Transverse	eqtl	1.0e-21	-0.33	7:100112961:A:AG
Skin Sun Exposed Lower leg	eqtl	1.9e-21	-0.21	7:100104017:T:C
Stomach	eqtl	2.1e-21	-0.39	7:100104017:T:C
Lung	eqtl	5.4e-21	-0.24	7:100102003:T:C
Adrenal Gland	eqtl	7.6e-21	-0.42	7:100102003:T:C
Cells Cultured fibroblasts	sqtl	1.0e-20	+0.48	7:100102003:T:C
Brain Cerebellum	eqtl	1.8e-19	-0.56	7:100073252:G:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
79926	4.0167	1637
79925	2.1991	1404
79924	1.0856	709

Top tissues by expression

showing 100 of 285 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	94.26	gold quality
right testis	UBERON:0004534	94.06	gold quality
right uterine tube	UBERON:0001302	92.35	gold quality
adenohypophysis	UBERON:0002196	90.62	gold quality
cortical plate	UBERON:0005343	90.49	gold quality
testis	UBERON:0000473	90.45	gold quality
stromal cell of endometrium	CL:0002255	90.35	gold quality
body of uterus	UBERON:0009853	90.03	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.28	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.21	gold quality
right lobe of thyroid gland	UBERON:0001119	89.19	gold quality
lower esophagus	UBERON:0013473	89.19	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.11	gold quality
ganglionic eminence	UBERON:0004023	88.87	gold quality
descending thoracic aorta	UBERON:0002345	88.53	gold quality
endocervix	UBERON:0000458	88.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.35	gold quality
pituitary gland	UBERON:0000007	88.35	gold quality
apex of heart	UBERON:0002098	88.30	gold quality
body of stomach	UBERON:0001161	88.13	gold quality
left lobe of thyroid gland	UBERON:0001120	88.12	gold quality
metanephros cortex	UBERON:0010533	88.04	gold quality
ectocervix	UBERON:0012249	87.86	gold quality
tibial nerve	UBERON:0001323	87.79	gold quality
thoracic aorta	UBERON:0001515	87.79	gold quality
ascending aorta	UBERON:0001496	87.74	gold quality
popliteal artery	UBERON:0002250	87.26	gold quality
tibial artery	UBERON:0007610	87.25	gold quality
aorta	UBERON:0000947	87.21	gold quality
left coronary artery	UBERON:0001626	87.13	gold quality
left uterine tube	UBERON:0001303	87.11	gold quality
left ovary	UBERON:0002119	87.02	gold quality
body of pancreas	UBERON:0001150	87.01	gold quality
right coronary artery	UBERON:0001625	86.93	gold quality
right ovary	UBERON:0002118	86.91	gold quality
transverse colon	UBERON:0001157	86.46	gold quality
esophagus	UBERON:0001043	86.39	gold quality
minor salivary gland	UBERON:0001830	86.10	gold quality
right lung	UBERON:0002167	86.04	gold quality
lower esophagus mucosa	UBERON:0035834	86.02	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.96	gold quality
thyroid gland	UBERON:0002046	85.83	gold quality
right frontal lobe	UBERON:0002810	85.82	gold quality
ventricular zone	UBERON:0003053	85.77	gold quality
upper lobe of left lung	UBERON:0008952	85.72	gold quality
mucosa of transverse colon	UBERON:0004991	85.53	gold quality
skin of abdomen	UBERON:0001416	85.36	gold quality
gall bladder	UBERON:0002110	85.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.29	gold quality
right atrium auricular region	UBERON:0006631	85.17	gold quality
stomach	UBERON:0000945	85.05	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.04	gold quality
skin of leg	UBERON:0001511	85.03	gold quality
mucosa of stomach	UBERON:0001199	84.99	gold quality
rectum	UBERON:0001052	84.80	gold quality
cerebellar hemisphere	UBERON:0002245	84.73	gold quality
coronary artery	UBERON:0001621	84.59	gold quality
esophagus mucosa	UBERON:0002469	84.56	gold quality
cerebellar cortex	UBERON:0002129	84.39	gold quality
gastrocnemius	UBERON:0001388	84.24	gold quality
right adrenal gland cortex	UBERON:0035827	84.12	gold quality
sigmoid colon	UBERON:0001159	83.91	gold quality
right adrenal gland	UBERON:0001233	83.82	gold quality
pancreas	UBERON:0001264	83.68	gold quality
muscle of leg	UBERON:0001383	83.66	gold quality
colonic epithelium	UBERON:0000397	83.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.55	gold quality
islet of Langerhans	UBERON:0000006	83.46	gold quality
sural nerve	UBERON:0015488	83.37	gold quality
left adrenal gland	UBERON:0001234	83.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.17	gold quality
left adrenal gland cortex	UBERON:0035825	83.14	gold quality
heart left ventricle	UBERON:0002084	83.12	gold quality
prefrontal cortex	UBERON:0000451	83.06	gold quality
vagina	UBERON:0000996	82.83	gold quality
small intestine	UBERON:0002108	82.82	gold quality
colon	UBERON:0001155	82.79	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.66	gold quality
omental fat pad	UBERON:0010414	82.65	gold quality
granulocyte	CL:0000094	82.56	gold quality
peritoneum	UBERON:0002358	82.54	gold quality
upper lobe of lung	UBERON:0008948	82.49	gold quality
intestine	UBERON:0000160	82.29	gold quality
smooth muscle tissue	UBERON:0001135	82.28	gold quality
cingulate cortex	UBERON:0003027	82.25	gold quality
large intestine	UBERON:0000059	82.16	gold quality
cardiac atrium	UBERON:0002081	82.11	gold quality
anterior cingulate cortex	UBERON:0009835	82.11	gold quality
ovary	UBERON:0000992	82.10	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.08	gold quality
cardiac ventricle	UBERON:0002082	82.07	gold quality
monocyte	CL:0000576	81.84	gold quality
saliva-secreting gland	UBERON:0001044	81.75	gold quality
heart	UBERON:0000948	81.46	gold quality
mouth mucosa	UBERON:0003729	81.37	gold quality
adipose tissue of abdominal region	UBERON:0007808	81.33	gold quality
subcutaneous adipose tissue	UBERON:0002190	81.29	gold quality
zone of skin	UBERON:0000014	81.28	gold quality
cerebellum	UBERON:0002037	81.09	gold quality
mononuclear cell	CL:0000842	81.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-124858	no	36.99
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Pituitary gland	tissue	14.7
Testis	tissue	14.5	high
Duodenum	tissue	11.6	medium
Skin 1	tissue	10.9	not detected
Seminal vesicle	tissue	10.4	not detected
Fallopian tube	tissue	10.2	low
Vagina	tissue	9.8	not detected
Esophagus	tissue	9.6	not detected
Pancreas	tissue	9.5	medium
Salivary gland	tissue	9.4	low
Basal ganglia	tissue	9.3	low
Heart muscle	tissue	9.2	low
Small intestine	tissue	9.2	medium
Choroid plexus	tissue	8.8
Postcentral gyrus	tissue	8.2
Endometrium 1	tissue	8.0	low
Putamen	tissue	8.0
Gallbladder	tissue	8.0	low
Thyroid gland	tissue	7.9	low
Stomach 1	tissue	7.8	medium
Caudate putamen	tissue	7.8
Skeletal muscle	tissue	7.7	not detected
Lung	tissue	7.7	low
Locus coeruleus	tissue	7.7
Hypothalamus	tissue	7.6
Spinal cord	tissue	7.6
Septum	tissue	7.6
Ovary	tissue	7.5	not detected
Smooth muscle	tissue	7.5	not detected
Prostate	tissue	7.5	not detected
Hippocampal formation	tissue	7.5
Periaqueductal gray	tissue	7.4
Medulla oblongata	tissue	7.3
Parathyroid gland	tissue	7.2	medium
Colon	tissue	7.2	low
Thalamus	tissue	7.2
Superior colliculi	tissue	7.2
Pons	tissue	7.1
Substantia nigra	tissue	7.1
Hippocampus	tissue	7.1	not detected
Corpus callosum	tissue	7.0
Midbrain	tissue	6.9
Urinary bladder	tissue	6.8	low
Ventral forebrain	tissue	6.8
Cervix	tissue	6.5	not detected
Frontal cortex	tissue	6.5
Adrenal gland	tissue	6.3	low
Amygdala	tissue	6.1
Cerebral cortex	tissue	6.0	low
Motor cortex	tissue	6.0
Nucleus accumbens	tissue	6.0
Temporal cortex	tissue	6.0
Lymph node	tissue	5.9	not detected
Rectum	tissue	5.8	low
Entorhinal cortex	tissue	5.8
Olfactory bulb	tissue	5.8
Somatosensory cortex	tissue	5.8
Retrosplenial cortex	tissue	5.8
Epididymis	tissue	5.7	not detected
Thymus	tissue	5.7

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Nucleus ambiguus (11.1), Blood vessel (10.7), Habenula (10.4), Nuclei of the trapezoid body (10.0), Piriform cortex (9.9).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting AP4M1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

23 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-6124	99.87	69.78	3551
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368
HSA-MIR-140-3P	99.04	67.69	1324
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-6125	95.17	67.26	91
HSA-MIR-6774-3P	89.14	65.20	68

Functional genomics

gnomAD constraint: pLI 5.01e-18, LOEUF 1.11, missense Z -0.185 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000359593 — one region, missense o/e 1.07.

Literature-anchored findings (GeneRIF, showing 9)

• Results show that AP-4 can bind different types of cytosolic signals known to mediate basolateral transport in epithelial cells. Depletion of mu 4 results in the mis-sorting of several proteins in epithelial cells. (PMID:11802162)
• AP-4 protein complex is involved in the regulation of somatodendritic-specific distribution of its cargo proteins including AMPA receptors. (PMID:18341993)
• In all five patients with autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G–>T), was identified. (PMID:19559397)
• analysis of the AP4M1 mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference [case report] (PMID:25496299)
• Here, the authors demonstrate that dileucine motifs in the hepatitis C virus NS2 protein mediate AP-1A, AP-1B, and AP-4 binding and cell-free virus release. Moreover, they reveal that AP-4, an adaptor not previously implicated in viral infections, mediates cell-to-cell spread and hepatitis C virus trafficking. (PMID:29535204)
• AP4M1 mutation is associated with hereditary spastic paraplegia. (PMID:30337681)
• A novel loss of function mutation in adaptor protein complex 4, subunit mu-1 causing autosomal recessive spastic paraplegia 50. (PMID:33884525)
• Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families. (PMID:36371792)
• Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia. (PMID:37758467)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ap4m1	ENSDARG00000056871
mus_musculus	Ap4m1	ENSMUSG00000019518
rattus_norvegicus	Ap4m1	ENSRNOG00000001353

Paralogs (7): AP3M2 (ENSG00000070718), AP1M1 (ENSG00000072958), AP1M2 (ENSG00000129354), STON2 (ENSG00000140022), AP2M1 (ENSG00000161203), AP3M1 (ENSG00000185009), STON1 (ENSG00000243244)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1337063) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 8 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased leukocyte cell number	1
increased hematocrit	1
increased circulating alanine transaminase level	1
increased circulating alkaline phosphatase level	1
increased circulating cholesterol level	1
increased circulating aspartate transaminase level	1
decreased circulating serum albumin level	1
increased circulating iron level	1

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
Canis lupus familiaris	E2RED8	96.9%	Diamond
Bos taurus	Q29RY8	96.9%	Diamond
Arabidopsis thaliana	Q9SB50	35.8%	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
CNPY4	protein-coding	245812
MIR106B	ncRNA	406900
MIR93	ncRNA	407050
MCM7	protein-coding	4176
TAF6	protein-coding	6878
MBLAC1	protein-coding	255374
LAMTOR4	protein-coding	389541
MIR25	ncRNA	407014
COPS6	protein-coding	10980
ZNF3	protein-coding	7551
ZSCAN21	protein-coding	7589

Protein

Protein identifiers

AP-4 complex subunit mu-1 — O00189 (reviewed: O00189)

Alternative names: AP-4 adaptor complex mu subunit, Adaptor-related protein complex 4 subunit mu-1, Mu subunit of AP-4, Mu-adaptin-related protein 2, Mu4-adaptin

All UniProt accessions (17): O00189, A0AAQ5BGV5, A0AAQ5BGV6, A0AAQ5BGY1, A0AAQ5BGY3, A0AAQ5BGY4, A0AAQ5BGY5, A0AAQ5BGZ1, A0AAQ5BH08, C9JC87, C9JMG3, C9JWL4, F8WCC5, F8WCR6, F8WDR3, H7BZV3, H7C0A0

UniProt curated annotations — full annotation on UniProt →

Function. Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways. AP-4 forms a non clathrin-associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system. It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons. Within AP-4, the mu-type subunit AP4M1 is directly involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos. The adaptor protein complex 4 (AP-4) may also recognize other types of sorting signal.

Subunit / interactions. Adaptor protein complex 4 (AP-4) is a heterotetramer composed of two large adaptins (epsilon-type subunit AP4E1 and beta-type subunit AP4B1), a medium adaptin (mu-type subunit AP4M1) and a small adaptin (sigma-type AP4S1). Interacts with tyrosine-based sorting signals on the cytoplasmic tail of cargo proteins such as APP, ATG9A, LAMP2 and NAGPA. Interacts with the C-terminal domain of GRID2. Interacts with GRIA1 and GRIA2; the interaction is indirect via CACNG3. Interacts with CACNG3; CACNG3 associates GRIA1 and GRIA2 with the adaptor protein complex 4 (AP-4) to target them to the somatodendritic compartment of neurons. Interacts with HOOK1 and HOOK2; the interactions are direct, mediate the interaction between FTS-Hook-FHIP (FHF) complex and AP-4 and the perinuclear distribution of AP-4.

Subcellular location. Golgi apparatus. trans-Golgi network membrane. Early endosome.

Tissue specificity. Ubiquitous. Highly expressed in testis and lowly expressed in brain and lung.

Disease relevance. Spastic paraplegia 50, autosomal recessive (SPG50) [MIM:612936] 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. SPG50 affected individuals present postnatally with early infantile hypotonia, delayed psychomotor development, strabismus, lack of independent walking and severe intellectual disability. They develop progressive spasticity of all limbs with generalized hypertonia, hyperreflexia, and extensor plantar responses by the end of the first year of life. Speech is absent or limited. Pseudobulbar signs, such as drooling, stereotypic laughter, and exaggerated jaw jerk, are part of the clinical picture. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the adaptor complexes medium subunit family.

RefSeq proteins (11): NP_001350600, NP_001425753, NP_001425754, NP_001425755, NP_001425756, NP_001425757, NP_001425758, NP_001425759, NP_001425760, NP_001425761, NP_004713* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001392	Clathrin_mu	Family
IPR011012	Longin-like_dom_sf	Homologous_superfamily
IPR018240	Clathrin_mu_CS	Conserved_site
IPR022775	AP_mu_sigma_su	Domain
IPR028565	MHD	Domain
IPR036168	AP2_Mu_C_sf	Homologous_superfamily
IPR050431	Adaptor_comp_med_subunit	Family

Pfam: PF00928, PF01217

UniProt features (29 total): strand 17, sequence conflict 4, turn 2, helix 2, mutagenesis site 2, chain 1, domain 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
3L81	Crystal structure of adaptor protein complex 4 (AP-4) mu4 subunit C-terminal domain, in …	X-RAY DIFFRACTION	1.6
4MDR	Crystal structure of adaptor protein complex 4 (AP-4) mu4 subunit C-terminal domain D190A …	X-RAY DIFFRACTION	1.85
9U9I	M4-CTD-undocked AP-4 core in apo form	ELECTRON MICROSCOPY	4
9U9J	M4-CTD-docked AP-4 core in apo form	ELECTRON MICROSCOPY	4.2
9U9R	ARF1(Q71L) bound M4-CTD-undocked AP-4 core	ELECTRON MICROSCOPY	6.6
9U9S	ARF1(Q71L) bound M4-CTD-docked AP-4 core	ELECTRON MICROSCOPY	6.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00189-F1	86.16	0.64

Human Protein Atlas

Protein class: Transporters, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

Functional residue map

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

Mutagenesis-validated functional residues (2)

Position	Phenotype
255	abolishes interaction with app.
283	strongly reduced interaction with app.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-432720	Lysosome Vesicle Biogenesis	curated
R-HSA-199991	Membrane Trafficking	—
R-HSA-5653656	Vesicle-mediated transport	—
R-HSA-199992	trans-Golgi Network Vesicle Budding	—

MSigDB gene sets: 313 (showing top): E2F_Q4, E2F_Q4_01, FREAC2_01, GOBP_LYSOSOMAL_TRANSPORT, E2F4DP1_01, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_TARGETING, GOBP_VACUOLAR_TRANSPORT, KEGG_LYSOSOME, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, FOXO1_01, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY

GO Biological Process (12): autophagosome assembly (GO:0000045), protein targeting (GO:0006605), protein targeting to lysosome (GO:0006622), intracellular protein transport (GO:0006886), post-Golgi vesicle-mediated transport (GO:0006892), Golgi to endosome transport (GO:0006895), intracellular protein localization (GO:0008104), vesicle-mediated transport (GO:0016192), Golgi to lysosome transport (GO:0090160), protein localization to basolateral plasma membrane (GO:1903361), protein transport (GO:0015031), protein transmembrane transport (GO:0071806)

GO Molecular Function (4): transmembrane protein transporter activity (GO:0008320), protein domain specific binding (GO:0019904), clathrin-cargo adaptor activity (GO:0035615), protein binding (GO:0005515)

GO Cellular Component (14): early endosome (GO:0005769), trans-Golgi network (GO:0005802), cytosol (GO:0005829), AP-1 adaptor complex (GO:0030121), AP-4 adaptor complex (GO:0030124), endosome lumen (GO:0031904), trans-Golgi network membrane (GO:0032588), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), clathrin-coated pit (GO:0005905), endomembrane system (GO:0012505), membrane (GO:0016020), clathrin adaptor complex (GO:0030131)

Reactome top-level categories

3 top-level categories:

Category	Pathways
trans-Golgi Network Vesicle Budding	1
Vesicle-mediated transport	1
Membrane Trafficking	1

GO top-level categories

49 GO namespaces:

Category	Terms
cellular anatomical structure	4
establishment of protein localization	2
lysosomal transport	2
intracellular protein localization	2
protein transport	2
cytosolic transport	2
transport	2
endosome	2
cytoplasm	2
AP-type membrane coat adaptor complex	2
endomembrane system	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
protein targeting to vacuole	1
protein localization to lysosome	1
intracellular transport	1
Golgi vesicle transport	1
post-Golgi vesicle-mediated transport	1
macromolecule localization	1
cellular process	1
Golgi to vacuole transport	1
protein localization to membrane	1
protein localization to cell periphery	1
transmembrane transport	1
macromolecule transmembrane transporter activity	1
protein transmembrane transport	1
protein transporter activity	1
protein binding	1
clathrin binding	1
cargo adaptor activity	1
binding	1
Golgi apparatus subcompartment	1
clathrin coat of trans-Golgi network vesicle	1
clathrin adaptor complex	1
intracellular organelle lumen	1
trans-Golgi network	1
organelle membrane	1
extracellular vesicle	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
membrane	1
vacuole	1
plasma membrane	1
clathrin coat	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 30 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
Golgi to endosome transport	BP	mutant phenotype
Golgi to lysosome transport	BP	direct assay
autophagosome assembly	BP	mutant phenotype
intracellular protein transport	BP	mutant phenotype
protein targeting	BP	direct assay
protein targeting to lysosome	BP	direct assay
AP-4 adaptor complex	CC	direct assay
extracellular exosome	CC	high-throughput assay
trans-Golgi network	CC	direct assay
protein domain specific binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,152 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AP4M1	AP4E1	Q9UPM8	968
AP4M1	AP4B1	Q9Y6B7	967
AP4M1	AP4S1	Q9Y587	966
AP4M1	AP5M1	Q9H0R1	883
AP4M1	GSTM1	P09488	873
AP4M1	KANK1	Q14678	789
AP4M1	ARF3	P16587	742
AP4M1	ARF1	P10947	734
AP4M1	RAP2B	P17964	724
AP4M1	AP3B2	Q13367	707
AP4M1	SEPSECS	Q9HD40	680
AP4M1	AP1B1	P78436	666
AP4M1	AP3D1	O14617	640
AP4M1	AP1G1	O43747	631
AP4M1	AP5Z1	O43299	581

IntAct

Human interaction partners of AP4M1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

15 partners by confidence:

Partner	Interaction type	MIscore	Records
TEPSIN	association	0.700	5
USP47	physical association	0.560	6
FNTA	physical association	0.560	5
DISC1	association	0.530	3
AP4E1	association	0.530	2
FHIP1A	physical association	0.520	1
HOOK1	physical association	0.370	4
HOOK2	physical association	0.370	2
CHTF8	physical association	0.370	1
DDX52	physical association	0.370	1
ECE1	physical association	0.370	1
ZBTB22	physical association	0.370	1
SUV39H2	association	0.350	2
AP4B1	association	0.350	1
SPRED2	association	0.350	1

BioGRID (75 interactions; top human partners by supporting records): AP4E1 (Affinity Capture-MS; 5 records), AP4B1 (Affinity Capture-MS; 3 records), ATG9A (Proximity Label-MS; 3 records), ENTHD2 (Affinity Capture-MS; 3 records), HOOK1 (Proximity Label-MS; 3 records), AP4S1 (Affinity Capture-MS; 2 records), ARF1 (Two-hybrid; 2 records), HOOK2 (Two-hybrid; 2 records), SUV39H2 (Affinity Capture-MS; 2 records), USP47 (Two-hybrid; 2 records), ACY1 (Affinity Capture-MS), AKT2 (Affinity Capture-MS), ARF5 (Proximity Label-MS), ARID2 (Affinity Capture-MS), ARPIN (Affinity Capture-MS)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
AP4M1	“form complex”	“AP-4 Adaptor complex”	binding

Protein complexes (CORUM) (1)

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

1 complexes by size:

Complex	Subunits	Members
AP4 adaptor complex	4	AP4B1, AP4E1, AP4M1, AP4S1

Disease & clinical

Genetic variants

Variant evidence for AP4M1: 612 ClinVar records (61 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	28
Uncertain significance	250
Likely benign	203
Benign	33

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 61 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
183357	NM_004722.4(AP4M1):c.952C>T (p.Arg318Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	11
561150	NM_004722.4(AP4M1):c.916C>T (p.Arg306Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	9
450739	NM_004722.4(AP4M1):c.218dup (p.Asn73fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
522944	NM_004722.4(AP4M1):c.802C>T (p.Arg268Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
429735	NM_004722.4(AP4M1):c.923C>G (p.Ser308Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
982098	NM_004722.4(AP4M1):c.547C>T (p.Gln183Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2415342	NM_004722.4(AP4M1):c.930-1G>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
280192	NM_004722.4(AP4M1):c.330C>G (p.Tyr110Ter)	Pathogenic	criteria provided, single submitter	2
818030	NM_004722.4(AP4M1):c.694dup (p.Glu232fs)	Pathogenic	criteria provided, single submitter	2
496933	NM_004722.4(AP4M1):c.737del (p.Pro246fs)	Pathogenic	criteria provided, single submitter	1
520808	NM_004722.4(AP4M1):c.727G>A (p.Gly243Ser)	Pathogenic	criteria provided, single submitter	1
973684	NM_004722.4(AP4M1):c.344_351dup (p.Asp118fs)	Pathogenic	criteria provided, single submitter	1
981457	NM_004722.4(AP4M1):c.974+2dup	Pathogenic	criteria provided, single submitter	1
1180679	NM_004722.4(AP4M1):c.53_54del (p.Lys18fs)	Pathogenic	criteria provided, single submitter	1
1285367	NM_004722.4(AP4M1):c.189_194delinsTCTC (p.Tyr65fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore AP4M1’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; 38 predictions of 1,144):

Position(s)	Effect	Δscore	Sites
7:100102661	acceptor_gain	1.0000
7:100102665	acceptor_gain	1.0000
7:100103402	acceptor_gain	1.0000
7:100103407–100103408	acceptor_loss	1.0000	5
7:100103520–100103521	donor_loss	1.0000	5
7:100105238–100105239	acceptor_loss	1.0000	5
7:100101969–100101970	donor_loss	0.9900	6
7:100102645–100102646	acceptor_gain	0.9900	3
7:100102673–100102674	acceptor_loss	0.9900	6
7:100102782–100102783	donor_loss	0.9900	5

AlphaMissense

1,111 missense substitutions predicted likely pathogenic (of 2,917 scored), across 312 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
D190	8	0.983	0.992
F409	8	0.981	0.998
D118	8	0.974	0.987
F155	8	0.965	0.994
F296	8	0.965	0.999
F255	8	0.964	0.997
N105	8	0.945	0.995
F264	8	0.942	0.997
F188	8	0.941	0.999
F378	8	0.939	0.998
F33	8	0.917	0.990
D92	8	0.896	0.961
D114	8	0.880	0.971
F234	8	0.862	0.992
D251	8	0.832	0.962
D19	8	0.824	0.927
F77	8	0.823	0.963
D320	8	0.795	0.906
W363	7	0.989	0.999
F423	7	0.988	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000265
Skin Cutaneous Melanoma (TCGA)	unfavorable	0.000588
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.00083

Disease associations

OMIM: gene MIM:602296 | disease phenotypes: MIM:612936, MIM:303350

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
hereditary spastic paraplegia 50	Definitive	Autosomal recessive	5
AP4-related intellectual disability and spastic paraplegia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
AP-4 deficiency syndrome	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (11 panels, 7 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

11 panels:

Panel	Rating
DDG2P	green
Hereditary spastic paraplegia	green
Hereditary spastic paraplegia, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Adult-onset neurological disorders	amber
Fetal anomalies	amber
Hereditary spastic paraplegia, adult onset	amber
Severe microcephaly	amber

Mondo (7): hereditary spastic paraplegia 50 (MONDO:0013048), congenital nervous system disorder (MONDO:0002320), microcephaly (MONDO:0001149), intellectual disability (MONDO:0001071), AP-4 deficiency syndrome (MONDO:0100176), hereditary spastic paraplegia (MONDO:0019064), (MONDO:0017241)

Orphanet (3): Severe intellectual disability and progressive spastic paraplegia (Orphanet:280763), Hereditary spastic paraplegia (Orphanet:685), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

54 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000280	Coarse facial features
HP:0000297	Facial hypotonia
HP:0000303	Mandibular prognathia
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000414	Bulbous nose
HP:0000486	Strabismus
HP:0000543	Optic disc pallor
HP:0000646	Amblyopia
HP:0000733	Motor stereotypy
HP:0001181	Adducted thumb
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001762	Talipes equinovarus
HP:0001763	Pes planus
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002120	Cerebral cortical atrophy
HP:0002171	Gliosis
HP:0002200	Pseudobulbar signs
HP:0002307	Drooling
HP:0002464	Spastic dysarthria
HP:0002465	Poor speech
HP:0002509	Limb hypertonia
HP:0002510	Spastic tetraplegia
HP:0002515	Waddling gait
HP:0002518	Abnormal periventricular white matter morphology
HP:0002761	Generalized joint hypermobility
HP:0002816	Genu recurvatum
HP:0003487	Babinski sign
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0007020	Progressive spastic paraplegia
HP:0008807	Acetabular dysplasia
HP:0010803	Everted upper lip vermilion
HP:0010864	Severe intellectual disability
HP:0012811	Wide nasal ridge
HP:0025502	Overweight
HP:0033683	Jaw hyperreflexia
HP:0100021	Cerebral palsy
HP:0100962	Excessive shyness

GWAS associations

3 associations:

Study	Trait	p-value
GCST010002_261	Refractive error	3e-16
GCST010703_241	Brain morphology (MOSTest)	6e-15
GCST010702_30	Subcortical volume (MOSTest)	6e-10

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
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
C567858	Spastic Paraplegia-50, Autosomal Recessive *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, increases methylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	increases expression	1
Diazinon	increases methylation	1
Drugs, Chinese Herbal	increases expression	1
Naphthoquinones	increases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Thiram	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

6 cell lines: 6 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A8KX	BCHNEUi007-A	Induced pluripotent stem cell	Male
CVCL_A8KY	BCHNEUi008-A	Induced pluripotent stem cell	Male
CVCL_A8KZ	BCHNEUi009-A	Induced pluripotent stem cell	Male
CVCL_A8LA	BCHNEUi010-A	Induced pluripotent stem cell	Male
CVCL_A8LB	BCHNEUi011-A	Induced pluripotent stem cell	Male
CVCL_A8LC	BCHNEUi012-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

showing 60 of 260 trials:

NCT	Phase	Status	Title
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
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT06692712	Phase 3	RECRUITING	Phase 3 Efficacy Study With Concurrent Control of IT MELPIDA in SPG50.Concurrent Controls.
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
NCT03961906	Phase 2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	Phase 2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT02304302	Phase 2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	Phase 2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	Phase 2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	Phase 2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06117020	Phase 1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT05273320	Phase 1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	Phase 1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	Phase 1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	Phase 1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	Phase 1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT05518188	Phase 1/2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (Serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	Phase 1/2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT02604186	Phase 2/3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT06478238	Early Phase 1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
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NCT06260982	Not specified	UNKNOWN	Cognitive Disorders in Hereditary Spastic Paraplegia Type 4
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NCT06573866	Not specified	ACTIVE_NOT_RECRUITING	Enhancement of Quality of Work And Life
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