PEX26
protein-codingperoxisomal biogenesis factor 26, the group of Peroxins
Gene summary
This gene belongs to the peroxin-26 gene family. It is probably required for protein import into peroxisomes. It anchors PEX1 and PEX6 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes. Defects in this gene are the cause of peroxisome biogenesis disorder complementation group 8 (PBD-CG8). PBD refers to a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. The PBD group is comprised of four disorders: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~27.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013938
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0019234
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013939
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0019234
Submitter: ClinGen
PEX26 was first reported in relation to autosomal recessive peroxisomal biogenesis disorder in 2003 (Matsumoto et al., PMID: 12851857). Numerous variants have been reported in humans per ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 14.5 points. Variants (nonsense, missense, and frameshift) in this gene have been reported in at least 12 probands in 3 publications (PMIDS: 12851857, 15542397, 15858711). More evidence is available in the literature, but the maximum score (12) for genetic evidence has been reached. The mechanism for disease is expected to be loss of function. This gene-disease association is supported by expression studies and in vitro functional assays. In summary, PEX26 is definitively associated with autosomal recessive peroxisomal biogenesis disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AR
Disease ID:MONDO:0013938
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013939
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0019609
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Renal
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PEX26 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001127649.3. 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 | 1 | 158 | 160 | ||
| missense | 13 | 193 | 10 | 2 | 218 | |
| nonsense | 9 | 7 | 16 | |||
| start loss | 1 | 2 | 3 | |||
| frameshift | 18 | 13 | 2 | 33 | ||
| splice donor/acceptor (+/-2bp) | 3 | 6 | 9 | |||
| Total | 31 | 42 | 196 | 168 | 2 | 439 |
Highest pathogenic variant AF is 0.00008674242
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001121121.1 | 5 | MANE Select | |
| Ensembl | ENSP00000382648.4 | 5 | MANE Select | |
| RefSeq | NP_001186248.1 | 4 | Standard | |
| RefSeq | NP_060399.1 | 5 | 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
- protein import into peroxisome matrix
- protein import into peroxisome membrane
Molecular Function
- protein binding
- protein C-terminus binding
- protein-containing complex binding
- ATPase binding
Cellular Component
- peroxisome
- peroxisomal membrane
- integral component of peroxisomal membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000329627
- Coding exons
- 5
- Length
- 53217
- Individuals with no LoFs
- 125728
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 20
- Defined
- 125748
- p
- 0.0000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.368 | 178 | 165 | 1.08 | 0.00000919 | 1913 |
| Missense (PolyPhen) | 51 | 60.562 | 0.84212 | 762 | ||
| Synonymous | -0.0326 | 73 | 72.6 | 1.00 | 0.00000373 | 656 |
| Loss of Function | 3.08 | 1 | 13.0 | 0.0772 | 6.60e-7 | 141 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00015 | 0.00014 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00011 | 0.000097 | rare |
| South Asian | 0.000068 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Probably required for protein import into peroxisomes. Anchors PEX1 and PEX6 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes. Involved in the import of catalase and proteins containing a PTS2 target sequence, but not in import of proteins with a PTS1 target sequence. {ECO:0000269|PubMed:12717447, ECO:0000269|PubMed:12851857}.;
- Disease
- DISEASE: Peroxisome biogenesis disorder 7A (PBD7A) [MIM:614872]: 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:12851857}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peroxisome biogenesis disorder 7B (PBD7B) [MIM:614873]: 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:12717447, ECO:0000269|PubMed:12851857}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.105
- RVIS EVS
- 1.13
- RVIS percentile EVS
- 92.16
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.797
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |