P4HB – Cole-Carpenter syndrome 1

In two unrelated individuals with Cole-Carpenter syndrome 1, whole-exome sequencing identified the heterozygous P4HB c.1178A>G (p.Tyr393Cys) variant. One arose de novo and the other was transmitted from a mosaic father, consistent with autosomal dominant inheritance. To date, three probands have been reported [PMID:25683117][PMID:29263160], with no additional segregating cases. This supports a Limited gene–disease association (three probands; one de novo, one mosaic; no segregation) and a Limited level of genetic evidence.

Functional studies demonstrate that the p.Tyr393Cys variant impairs PDIA1 oxidoreductase activity in vitro. Molecular dynamics simulations revealed significant conformational changes at the active-site region [PMID:32352225]. Furthermore, a P4hbC402R/+ mouse model exhibits enhanced ER stress, PERK activation, and defective chondrocyte proliferation leading to long bone shortening, recapitulating key CSS1 features [PMID:39778777]. These data provide Moderate functional evidence for a dominant-negative or haploinsufficient mechanism.

Key Take-home: The recurrent p.Tyr393Cys variant in P4HB underlies autosomal dominant CSS1 through structural destabilization and ER stress, supporting molecular diagnosis and informing potential ER stress–modulating therapies.

References

• American journal of human genetics • 2015 • Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. PMID:25683117
• Journal of medical genetics • 2018 • P4HB recurrent missense mutation causing Cole-Carpenter syndrome. PMID:29263160
• Chemical biology & drug design • 2020 • A molecular dynamics approach on the Y393C variant of protein disulfide isomerase A1. PMID:32352225
• Biochimica et biophysica acta. Molecular basis of disease • 2025 • Endoplasmic reticulum stress causes long bone shortening in P4hbC402R/+ mice: A mouse model exhibiting significant features of cole-carpenter syndrome driven by P4HB mutations. PMID:39778777

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