GeneBe

PEX5

protein-coding

peroxisomal biogenesis factor 5, the group of Peroxins|Tetratricopeptide repeat domain containing

Gene summary

The product of this gene binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause of neonatal adrenoleukodystrophy (NALD), a cause of Zellweger syndrome (ZWS) as well as may be a cause of infantile Refsum disease (IRD). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

Previous symbols:
  • PXR1

MANE transcript

NM_001351132.2

Inheritance

AR

ClinVar variants

P:79U:363B:281

Top phenotype

Peroxisome biogenesis disorder 2A (Zellweger syndrome); Peroxisome biogenesis disorder 2B; Rhizomelic chondrodysplasia punctata, type 5

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr12:7,188,685-7,218,574

External References & Databases

Ensembl (ENSG00000139197)NCBI Gene (5830)OMIM (600414)HGNC:9719GenCCUniProt (P50542)AlphaFoldClinVar (PEX5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~29.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

rhizomelic chondrodysplasia punctata type 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014743

Submitter: Labcorp Genetics (formerly Invitae)

peroxisome biogenesis disorder 2A (Zellweger)STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008954

Submitter: Labcorp Genetics (formerly Invitae)

peroxisome biogenesis disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019234

Submitter: PanelApp Australia

peroxisome biogenesis disorder 2A (Zellweger)DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008954

Submitter: G2P

rhizomelic chondrodysplasia punctata type 5SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014743

Submitter: Orphanet

peroxisome biogenesis disorder 2A (Zellweger)MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008954

Submitter: Ambry Genetics

rhizomelic chondrodysplasia punctata type 5LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014743

Submitter: Ambry Genetics

peroxisome biogenesis disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019234

Submitter: ClinGen

The relationship between PEX5 and autosomal recessive peroxisome biogenesis disorder was first reported in 1995, (Dodt et al., PMID:7719337). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case-level and experimental data: 12.5 points. There are five patients reported in the literature with variants (nonsense, frameshift, and missense) (PMID: 26220973, PMID: 7719337, PMID: 27290639). This gene-disease association is supported by in vitro functional assays and animal models. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern, and phenotypic variability underlying the disease entities: (1) Peroxisome biogenesis disorder 2A (MIM: 214110), (2) Peroxisome biogenesis disorder 2B (MIM: 202370), and (3) Rhizomelic chondrodysplasia punctata, type 5 (MIM: 616716). Therefore, all of the disease entities have been lumped into one disease entity, Peroxisome Biogenesis Disorder. In summary, PEX5 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.

peroxisome biogenesis disorder 2BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008736

Submitter: G2P

Zellweger spectrum disordersSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019609

Submitter: Orphanet

Clinical Genomic Database (CGD)

Peroxisome biogenesis disorder 2A (Zellweger syndrome); Peroxisome biogenesis disorder 2B; Rhizomelic chondrodysplasia punctata, type 5AR

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

Refs: 7719337; 26220973Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PEX5 variants in ClinVar

17 Conditions Cataloged
Peroxisome biogenesis disorder 2BTotal: 911
not providedTotal: 154
PEX5-related disorderTotal: 122
not specifiedTotal: 115
Inborn genetic diseasesTotal: 95
Peroxisome biogenesis disorder 2A (Zellweger)Total: 79
Rhizomelic chondrodysplasia punctata type 5Total: 27
Peroxisome biogenesis disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001351132.2. 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.

EffectPLPVUSLBBSum
synonymous
7
clinvar
271
clinvar
1
clinvar
 279
missense
1
clinvar
4
clinvar
343
clinvar
6
clinvar
2
clinvar
 356
nonsense
13
clinvar
10
clinvar
1
clinvar
 24
start loss
1
clinvar
 1
frameshift
25
clinvar
8
clinvar
4
clinvar
 37
splice donor/acceptor (+/-2bp)
18
clinvar
7
clinvar
1
clinvar
 26
Total39403632783723

Highest pathogenic variant AF is 0.000015740854

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 175 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001351132.2RefSeqNP_001338061.115MANE Select
ENST00000675855.1EnsemblENSP00000502374.115MANE Select
NM_000319.5RefSeqNP_000310.215Standard
NM_001131023.2RefSeqNP_001124495.115Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Peroxisome - Homo sapiens (human)
  • Post-translational protein modification
  • Metabolism of proteins
  • Peroxisomal protein import
  • Protein ubiquitination

Biological Process

  • protein targeting to peroxisome
  • protein import into peroxisome matrix
  • protein import into peroxisome matrix, docking
  • protein ubiquitination
  • protein import into peroxisome membrane

Molecular Function

  • peroxisome targeting sequence binding
  • peroxisome matrix targeting signal-1 binding
  • protein binding
  • enzyme binding
  • small GTPase binding

Cellular Component

  • cytoplasm
  • peroxisome
  • peroxisomal membrane
  • Golgi apparatus
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000434354
Coding exons
15
Length
29890
Individuals with no LoFs
125711
Homozygous LoFs
0
Heterozygous LoFs
37
Defined
125748
p
0.000147
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6813253610.8990.00002264231
Missense (PolyPhen)71100.240.708321293
Synonymous-0.2811491451.030.000008371323
Loss of Function3.511437.10.3780.00000203408

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.000170.00014rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.000190.00019rare
South Asian0.000130.00013rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import. {ECO:0000269|PubMed:7706321, ECO:0000269|PubMed:7719337, ECO:0000269|PubMed:7790377}.;
Disease
DISEASE: Peroxisome biogenesis disorder 2A (PBD2A) [MIM:214110]: A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and characterized clinically 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:7719337}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peroxisome biogenesis disorder 2B (PBD2B) [MIM:202370]: 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:10462504, ECO:0000269|PubMed:7719337}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Rhizomelic chondrodysplasia punctata 5 (RCDP5) [MIM:616716]: A form of rhizomelic chondrodysplasia punctata, a disease characterized by severely disturbed endochondral bone formation, rhizomelic shortening of femur and humerus, vertebral disorders, dwarfism, cataract, cutaneous lesions, facial dysmorphism, and severe mental retardation with spasticity. {ECO:0000269|PubMed:26220973}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.321

Intolerance Scores

LoFtool
0.0644
RVIS EVS
-0.84
RVIS percentile EVS
11.36

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.697

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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