AP4E1

protein-coding

adaptor related protein complex 4 subunit epsilon 1, the group of Clathrin/coatomer adaptor, adaptin-like, N-terminal domain containing|Adaptor related protein complex 4

Gene summary

This gene encodes a member of the adaptor complexes large subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is a large subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Disruption of this gene may be associated with cerebral palsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

MANE transcript

NM_007347.5

Inheritance

AR, AD

ClinVar variants

P:35U:334B:148

Top phenotype

Stuttering, familial persistent, 1; Spastic paraplegia 51, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr15:50,908,672-51,005,895

External References & Databases

Ensembl (ENSG00000081014)

Transcript & Mutation Effects

hg38 • Region Span ~97.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 51MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013401

Submitter: Ambry Genetics

AP4-related intellectual disability and spastic paraplegiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017241

Submitter: Orphanet

hereditary spastic paraplegia 51STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013401

Submitter: PanelApp Australia

AP-4 deficiency syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100176

Submitter: ClinGen

AP4E1 loss-of-function variants have been reported in at least 21 individuals from 11 families with autosomal recessive Adaptor Protein 4 (AP4) deficiency syndrome (PMID: 32979048). AP4 deficiency results in severe early-onset developmental delay with motor delay and speech delay, intellectual disability, hypotonia in infancy followed by spastic paraplegia and later tetraplegia, microcephaly, and seizures (PMID: 32979048, 30543385). Biallelic AP4E1 nonsense, frameshift, splicing and large deletion variants leading to loss of AP4E1 protein function and the AP4 complex have been reported in AP4 deficiency syndrome patients (PMID: 32979048, 21620353, 20972249, 21937992, 23472171). The gene-disease association is further supported by biochemical and functional assays demonstrating loss of AP4 complex function and impaired protein trafficking in fibroblasts from patients with AP4E1 loss-of-function variants (PMID: 31915823). AP4E1 knockout mice demonstrate impaired motor coordination, weak grip strength, thin corpus callosum and impaired protein trafficking, which is consistent with features of AP4 deficiency syndrome (PMID: 29698489). In summary, the AP4E1 gene is definitively associated with autosomal recessive AP4 deficiency syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on December 16, 2020. As of July 2024, this record underwent administrative updates to update scoring to be consistent with SOP Version 10.

hereditary spastic paraplegia 51DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013401

Submitter: G2P

hereditary spastic paraplegia 51STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013401

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Stuttering, familial persistent, 1; Spastic paraplegia 51, autosomal recessiveAD/AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21620353; 20972249; 21937992; 24700674; 26544806

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP4E1 variants in ClinVar

16 Conditions Cataloged

Spastic paraplegiaTotal: 407

Inborn genetic diseasesTotal: 139

not providedTotal: 135

not specifiedTotal: 84

Hereditary spastic paraplegia 51Total: 31

Hereditary spastic paraplegiaTotal: 30

AP4E1-related disorderTotal: 23

Stuttering, familial persistent, 1Total: 19

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007347.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	121 clinvar	1 clinvar	131
missense		1 clinvar	320 clinvar	23 clinvar	1 clinvar	345
nonsense	6 clinvar	2 clinvar				8
start loss			1 clinvar			1
frameshift	7 clinvar	11 clinvar	1 clinvar			19
splice donor/acceptor (+/-2bp)	1 clinvar	7 clinvar	3 clinvar	2 clinvar		13
Total	14	21	334	146	2	517

Highest pathogenic variant AF is 0.000012391343

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007347.5	RefSeq	NP_031373.2	21	MANE Select
ENST00000261842.10	Ensembl	ENSP00000261842.5	21	MANE Select
NM_001252127.2	RefSeq	NP_001239056.1	19	Standard
ENST00000558439.5	Ensembl	ENSP00000452712.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Golgi Associated Vesicle Biogenesis
Lysosome Vesicle Biogenesis
Clathrin derived vesicle budding
trans-Golgi Network Vesicle Budding

Biological Process

protein targeting
protein localization
vesicle-mediated transport

Molecular Function

protein binding

Cellular Component

AP-4 adaptor complex
endosome lumen
trans-Golgi network membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261842
Coding exons: 21
Length: 97229
Individuals with no LoFs: 125662
Homozygous LoFs: 0
Heterozygous LoFs: 86
Defined: 125748
p: 0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.521	532	567	0.938	0.0000260	7414
Missense (PolyPhen)		171	203.74	0.8393		2737
Synonymous	-0.490	223	214	1.04	0.0000105	2162
Loss of Function	4.98	16	56.3	0.284	0.00000277	751

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00038	0.00038	rare
South Asian	0.00088	0.00088	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (PubMed:10066790, PubMed:10436028). 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. AP-4 is involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos, but may also recognize other types of sorting signal (Probable). {ECO:0000269|PubMed:10066790, ECO:0000269|PubMed:10436028, ECO:0000305|PubMed:10066790, ECO:0000305|PubMed:10436028}.;
Disease: DISEASE: Stuttering, familial persistent 1 (STUT1) [MIM:184450]: A familial form of stuttering, a disturbance in the normal fluency and time patterning of speech, characterized by frequent repetitions or prolongations of sounds or syllables, and by interruptions of speech known as blocks. STUT1 inheritance is autosomal dominant. {ECO:0000269|PubMed:26544806}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0996

Intolerance Scores

LoFtool: 0.691
RVIS EVS: -0.66
RVIS percentile EVS: 16.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.639

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium