AP5Z1

protein-coding

adaptor related protein complex 5 subunit zeta 1, the group of Armadillo like helical domain containing|Adaptor related protein complex 5

Gene summary

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). [provided by RefSeq, Jan 2011]

Previous symbols:

KIAA0415

MANE transcript

NM_014855.3

Inheritance

ClinVar variants

P:75U:464B:285

Top phenotype

Spastic paraplegia 48, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 1.14

Max pathogenic AF

—

Genomic locus

chr7:4,775,615-4,794,397

External References & Databases

Ensembl (ENSG00000242802)

Transcript & Mutation Effects

hg38 • Region Span ~18.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 48STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013342

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 48MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013342

Submitter: Genomics England PanelApp

hereditary spastic paraplegia 48STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013342

Submitter: PanelApp Australia

hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: ClinGen

The AP5Z1 gene is located on chromosome 7 at 7p21.3. It encodes the zeta subunit of the adaptor-related protein complex-5, a component of the adaptor-related protein complex-5, which localizes in the late endosomes were facilitates vesicle-mediated intracellular sorting and trafficking of selected transmembrane cargo proteins. AP5Z1 was first reported in relation to autosomal recessive hereditary spastic paraplegia (HSP) in 2010 (Słabicki et al., PMID: 20613862). The disorder is a slowly progressive complex spastic paraplegia of the lower limbs accompanied by other phenotypic features, including ataxia, seizures, intellectual disability, muscle atrophy, extrapyramidal disturbance, and peripheral neuropathy. Onset is typically between 10 and 59 years of age, and affected individuals often become wheelchair-dependent. Multiple unique variants have been reported in at least 21 individuals in numerous publications (PMID: 20613862, 26085577, 33543803, 27606357, 31289639). Variants in this gene segregated with the disorder in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) was reached. Most reported variants are LoF (PMID:33543803, 20613862, 2608557) but missense variants have also been identified in several cases (PMID:24833714). Functional evidence, including immunohistochemistry and protein expression studies, supports the assumption that these variants are responsible for the patient's phenotype by acting through a loss of function mechanism (PMID:33543803). Mutations in the AP5Z1 gene lead to transport defects from late endosomes to the trans-Golgi network. In vitro experiments conducted in patient's fibroblasts and knockout mouse embryonic fibroblasts (MEFs) revealed a generalized autophagy defect under stress conditions manifested with an increased number of autophagosomes and decreased lysosome counts (PMID: 31289639, 27606357). The lysosome depletion and impaired autophagic clearance ultimately lead to aberrant multilamellar toxic storage material accumulation. The gene-disease relationship is additionally supported by AP5Z1 knockout mice that recapitulate most of the features seen in HSP patients (Khundadze M et al., 2019, PMID: 30930081). In summary, there is definitive evidence to support the relationship between the AP5Z1 gene and autosomal recessive hereditary spastic paraplegia. This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 09/19/2022 (SOP Version 9).

hereditary spastic paraplegia 48SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013342

Submitter: Orphanet

hereditary spastic paraplegia 48MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013342

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spastic paraplegia 48, autosomal recessiveAR

Manifestation: 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: 20613862; 22554690

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AP5Z1 variants in ClinVar

12 Conditions Cataloged

Hereditary spastic paraplegia 48Total: 729

not providedTotal: 284

Inborn genetic diseasesTotal: 247

Hereditary spastic paraplegiaTotal: 91

not specifiedTotal: 88

AP5Z1-related disorderTotal: 41

Retinal dystrophyTotal: 22

Macular dystrophy with or without extraocular featuresTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014855.3. 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		1 clinvar	15 clinvar	245 clinvar	8 clinvar	269
missense		2 clinvar	438 clinvar	30 clinvar	1 clinvar	471
nonsense	5 clinvar	17 clinvar				22
start loss						0
frameshift	16 clinvar	17 clinvar	6 clinvar	1 clinvar		40
splice donor/acceptor (+/-2bp)	1 clinvar	16 clinvar	5 clinvar			22
Total	22	53	464	276	9	824

Highest pathogenic variant AF is 0.00013782906

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014855.3	RefSeq	NP_055670.1	17	MANE Select
ENST00000649063.2	Ensembl	ENSP00000497815.1	17	MANE Select
NM_001364858.1	RefSeq	NP_001351787.1	14	Standard
ENST00000647984.1	Ensembl	ENSP00000497794.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

double-strand break repair via homologous recombination
protein transport
endosomal transport

Molecular Function

protein binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
nuclear speck
AP-type membrane coat adaptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000348624
Coding exons: 17
Length: 18691
Individuals with no LoFs: 124560
Homozygous LoFs: 0
Heterozygous LoFs: 185
Defined: 124745
p: 0.000742

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.97	700	511	1.37	0.0000354	5064
Missense (PolyPhen)		197	132.74	1.4841		1313
Synonymous	-7.62	407	253	1.61	0.0000191	1758
Loss of Function	-0.793	43	37.7	1.14	0.00000216	375

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0010	0.0010	notable
Latino/Admixed American	0.00041	0.00041	rare
Ashkenazi Jewish	0.00071	0.00070	rare
East Asian	0.00091	0.00089	rare
Finnish	0.00044	0.00042	rare
European (Non-Finnish)	0.00095	0.00092	rare
South Asian	0.00063	0.00059	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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. {ECO:0000269|PubMed:20613862, ECO:0000269|PubMed:22022230}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:20613862}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

RVIS EVS: -0.6
RVIS percentile EVS: 17.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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