PEX6

protein-coding

peroxisomal biogenesis factor 6, the group of Peroxins|AAA ATPases

Gene summary

This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

MANE transcript

NM_000287.4

Inheritance

AR, AD

ClinVar variants

P:357U:623B:653

Top phenotype

Heimler syndrome 2 (Peroxisome biogenesis disorder 4C)

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr6:42,963,865-42,979,181

External References & Databases

Ensembl (ENSG00000124587)

Transcript & Mutation Effects

hg38 • Region Span ~15.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive cerebellar ataxia-blindness-deafness syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010061

Submitter: Orphanet

peroxisome biogenesis disorder 4A (Zellweger)DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013930

Submitter: G2P

peroxisome biogenesis disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019234

Submitter: ClinGen

The relationship between PEX6 and peroxisome biogenesis disorder (types 4A and 4B and Heimler syndrome included), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of August, 2019. PEX6 encodes a cystolic AAA protein (ATPase associated with diverse cellular activities) and is required for stability of the cytoplasmic PTS1 receptor (Yahraus et al., 1996; PMID 8670792). Peroxisomal biogenesis disorders are caused by defects in various stages of peroxisomal protein import and/or peroxisome biogenesis. There are at least 14 PEX genes implicated in peroxisome biogenesis disorders, with PEX6 being the second most commonly affected gene in patients with a frequency of ~14.5% (Steinberg et al., 2003; PMID 20301621). Variants in PEX6 were first reported in humans with peroxisomal biogenesis disorder in 1996 (Yahraus et al., PMID 8670792). Data from 10 patients with 9 unique variants (missense, nonsense, frameshift, splicing) from 4 publications were curated (Krause et al., 2006, PMID 17041890; Levesque et al., 2012, PMID 22894767; Ratbi et al., 2015, PMID 26387595; Yahraus et al., 1996, PMID 8670792). Additional cases are available in the literature but the maximum score for genetic evidence (12 points) has been reached. The relationship between PEX6 and peroxisome biogenesis disorder is supported by experimental evidence including a biochemical function similar to other PEX genes implicated in peroxisome biogenesis disorders (Waterham et al., 2012, PMID 22871920), in vitro assays (Levesque et al., 2012, PMID 22894767), and a protein interaction with PEX1 (Matsumoto et al., 2003, PMID 12717447), which is encoded by a known peroxisome biogensies disorder gene. In summary, PEX6 is definitively associated with peroxisome biogenesis disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Peroxisomal Disorders Gene Curation Expert Panel on September 6, 2019.

Perrault syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0017312

Submitter: PanelApp Australia

peroxisome biogenesis disorder 4A (Zellweger)DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013930

Submitter: Myriad Women's Health

Heimler syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014709

Submitter: G2P

Zellweger spectrum disordersSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019609

Submitter: Orphanet

peroxisome biogenesis disorder due to PEX6 defectDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100263

Submitter: Natera

peroxisome biogenesis disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0019234

Submitter: PanelApp Australia

peroxisome biogenesis disorder 4BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013931

Submitter: G2P

peroxisome biogenesis disorder 4A (Zellweger)STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013930

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Heimler syndrome 2 (Peroxisome biogenesis disorder 4C)AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Audiologic/Otolaryngologic

Rationale: Heimler syndrome 2, representing a mild peroxisomal biogenesis disorder, includes sensorineural hearing loss among other features, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 8940266; 8670792; 10408779; 11355018; 16530715; 17041890; 19877282; 21937992; 22894767; 26387595

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PEX6 variants in ClinVar

27 Conditions Cataloged

Peroxisome biogenesis disorderTotal: 1622

not providedTotal: 291

Zellweger spectrum disordersTotal: 253

PEX6-related disorderTotal: 238

Peroxisome biogenesis disorder 4A (Zellweger)Total: 205

Heimler syndrome 2Total: 178

not specifiedTotal: 153

Inborn genetic diseasesTotal: 146

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000287.4. 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			21 clinvar	622 clinvar	1 clinvar	644
missense	5 clinvar	39 clinvar	593 clinvar	29 clinvar		666
nonsense	31 clinvar	33 clinvar	1 clinvar			65
start loss	3 clinvar	3 clinvar				6
frameshift	76 clinvar	109 clinvar	3 clinvar			188
splice donor/acceptor (+/-2bp)	8 clinvar	50 clinvar	5 clinvar	1 clinvar		64
Total	123	234	623	652	1	1633

Highest pathogenic variant AF is 0.0030894591

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000287.4	RefSeq	NP_000278.3	17	MANE Select
ENST00000304611.13	Ensembl	ENSP00000303511.8	17	MANE Select
NM_001316313.2	RefSeq	NP_001303242.1	17	Standard
ENST00000244546.4	Ensembl	ENSP00000244546.4	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Peroxisome - Homo sapiens (human)
Metabolism of proteins
Peroxisomal protein import

Biological Process

protein targeting to peroxisome
peroxisome organization
protein import into peroxisome matrix
protein import into peroxisome matrix, translocation
protein stabilization

Molecular Function

protein binding
ATP binding
protein C-terminus binding
ATPase activity
ATPase activity, coupled

Cellular Component

photoreceptor outer segment
cytoplasm
peroxisome
peroxisomal membrane
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304611
Coding exons: 17
Length: 15351
Individuals with no LoFs: 125617
Homozygous LoFs: 0
Heterozygous LoFs: 131
Defined: 125748
p: 0.000521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.44	436	529	0.824	0.0000311	6093
Missense (PolyPhen)		139	183.72	0.75659		2149
Synonymous	0.362	220	227	0.969	0.0000120	2268
Loss of Function	3.21	15	35.7	0.421	0.00000167	443

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.00045	0.00032	rare
European (Non-Finnish)	0.00064	0.00063	rare
South Asian	0.0010	0.0010	notable
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in peroxisome biosynthesis. Required for stability of the PTS1 receptor. Anchored by PEX26 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes.;
Disease: DISEASE: Peroxisome biogenesis disorder 4A (PBD4A) [MIM:614862]: A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and clinically characterized by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life. {ECO:0000269|PubMed:10408779, ECO:0000269|PubMed:8670792}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peroxisome biogenesis disorder 4B (PBD4B) [MIM:614863]: A peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid. {ECO:0000269|PubMed:11355018}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Heimler syndrome 2 (HMLR2) [MIM:616617]: A form of Heimler syndrome, a very mild peroxisome biogenesis disorder characterized by sensorineural hearing loss, amelogenesis imperfecta resulting in enamel hyoplasia of the secondary dentition, nail defects, and occasional or late-onset retinal pigmentation abnormalities. {ECO:0000269|PubMed:19105186, ECO:0000269|PubMed:26387595, ECO:0000269|PubMed:27302843}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.206

Intolerance Scores

LoFtool: 0.114
RVIS EVS: 1.14
RVIS percentile EVS: 92.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.452

Gene Damage Prediction

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