PEX5 – Rhizomelic Chondrodysplasia Punctata Type 5

Rhizomelic chondrodysplasia punctata type 5 (RCDP5) is an autosomal recessive peroxisome biogenesis disorder characterized by proximal limb shortening (rhizomelia) and punctate calcifications in cartilage (HP:0009829, HP:0000912). The PEX5 gene encodes two isoforms, PEX5L and PEX5S, which mediate import of peroxisomal matrix proteins carrying PTS1 or PTS2 targeting signals. Loss of PEX5L selectively impairs PTS2‐dependent import, phenocopying defects seen in PEX7‐related RCDP1 but sparing PTS1 import. Given this isoform‐specific mechanism, PEX5 is now established as the causal gene for RCDP5, expanding the spectrum of peroxisomal biogenesis disorders beyond the traditional Zellweger spectrum.

Genetic evidence for PEX5 in RCDP5 comes from four affected individuals in two unrelated families who are homozygous for a frameshift variant c.722dupA (p.Val242GlyfsTer33) in exon 9, unique to the PEX5L isoform (PMID:26220973). This variant segregates with disease in both families and was absent in ethnically matched controls. No other variant classes have been reported to date, indicating a founder or recurrent LoF allele restricted to PEX5L. The autosomal recessive inheritance and consistency across unrelated pedigrees support a robust genetic association.

Inheritance is autosomal recessive; four probands presented with classic RCDP features and two additional siblings were affected, confirming familial segregation. The sole reported pathogenic change is a loss‐of‐function frameshift mutation affecting PEX5L, with no missense or deep‐intronic alleles described, suggesting haploinsufficiency or null mechanism.

Functional data demonstrate that expression of wild-type PEX5L in patient fibroblasts fully restores import of PTS2‐tagged proteins, whereas PTS1 import remains intact, confirming isoform-specific receptor function and rescue of the cellular phenotype (PMID:26220973). This rescue experiment provides direct evidence of pathogenicity and clarifies the mechanistic basis of RCDP5. Complementary CHO cell studies of PEX5 mutants and isoform interactions further delineate the structural requirements for PTS2 import.

No conflicting reports have disputed PEX5’s role in RCDP5; all evidence converges on a single mechanism. Additional reports of PEX5 in general peroxisome biogenesis disorders further contextualize the phenotype but exceed the scope of RCDP5–specific scoring.

In summary, PEX5L‐specific LoF mutations cause RCDP5 through selective loss of peroxisomal targeting signal type 2 import, with clear genetic and functional concordance. Genetic testing of PEX7 and exon 9 of PEX5 is recommended in patients with isolated PTS2 import defects. Key take-home: testing for PEX5L exon 9 mutations is clinically useful for diagnosing RCDP5 and guiding carrier screening and therapeutic research.

References

• Human molecular genetics • 2015 • A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. PMID:26220973

Evidence Based Scoring (AI generated)