PEX7 – Peroxisome Biogenesis Disorder

PEX7 encodes the cytosolic peroxisomal targeting signal 2 (PTS2) receptor and is causally implicated in autosomal recessive peroxisome biogenesis disorders (PBDs), most prominently rhizomelic chondrodysplasia punctata type 1 (RCDP1) within the peroxisome biogenesis disorder spectrum (PMID:9090381). Loss of PEX7 function disrupts import of PTS2‐bearing enzymes, leading to plasmalogen deficiency and the characteristic skeletal dysplasia, cataracts, and neurodevelopmental delay seen in RCDP1.

Inheritance is autosomal recessive with segregation documented in at least 5 affected sib pairs in a cohort of 78 probands, confirming familial transmission of PEX7 variants (PMID:11781871). Over 100 unrelated individuals with RCDP1 have been reported, carrying biallelic PEX7 variants that include missense, nonsense, frameshift, and splice‐site mutations.

The variant spectrum comprises hypomorphic and null alleles. A founder allele, c.875T>A (p.Leu292Ter), accounts for ~50% of PEX7 mutations and arose on a single ancestral haplotype (PMID:10673331). Other recurrent missense changes include c.649G>A (p.Gly217Arg) and c.653C>T (p.Ala218Val), which exhibit residual activity correlating with milder phenotypes.

Functional studies demonstrate that wild-type PEX7 restores PTS2 import in patient fibroblasts and in PEX7‐deficient CHO lines, whereas RCDP1-associated alleles uniformly fail to complement the import defect (PMID:9090381, PMID:12054588). Structural modelling and binding assays further delineate a conserved PTS2-binding groove in PEX7, confirming a loss-of-function mechanism.

No significant conflicting evidence has been reported; phenotypic variability aligns with allele‐specific residual activity. Together, the genetic, biochemical, and cell‐based rescue data fulfil criteria for a definitive gene–disease relationship.

Key Take-home: PEX7 biallelic loss-of-function variants cause autosomal recessive peroxisome biogenesis disorder with RCDP1 features, and diagnostic testing should include sequencing of PEX7 to guide genetic counseling and future therapeutic development.

References

• Nature Genetics • 1997 • Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata PMID:9090381
• American Journal of Human Genetics • 2002 • Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1 PMID:11781871
• Genomics • 2000 • PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter PMID:10673331

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