P4HB – Prolyl 4-Hydroxylase Subunit Beta in Cole-Carpenter Syndrome

Cole-Carpenter syndrome (CCS) is a rare autosomal-dominant osteogenesis imperfecta–like disorder characterized by severe bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features.

The etiology of CCS was traced to a recurrent heterozygous missense mutation, c.1178A>G (p.Tyr393Cys), in exon 9 of P4HB, identified initially in two unrelated individuals (PMID:25683117) and subsequently in an Asian patient (PMID:30063094) and a separate severe OI case (PMID:29263160), totaling four unrelated probands.

All reported cases exhibit autosomal dominant inheritance with de novo occurrence in three probands and one mosaic paternal transmission; no additional affected relatives segregating the variant have been documented.

Clinical manifestations uniformly include recurrent long-bone fractures with metaphyseal sclerosis, craniosynostosis, ocular proptosis, hydrocephalus, midface hypoplasia, and scoliosis.

Functional assays reveal that the p.Tyr393Cys substitution impairs PDI disulfide isomerase activity, induces endoplasmic reticulum stress in patient fibroblasts, and perturbs collagen matrix assembly without reducing type I collagen secretion (PMID:25683117).

A knock-in mouse model carrying the orthologous P4hbC402R mutation recapitulates long bone shortening via defective chondrocyte proliferation and hypertrophy driven by enhanced ER stress and PERK pathway activation (PMID:39778777).

Genetic and experimental concordance support a dominant-negative mechanism of P4HB missense mutations as a definitive cause of CCS. Early molecular diagnosis enables timely bisphosphonate therapy to strengthen bone and improve outcomes.

References

• American Journal of Human Genetics • 2015 • Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB. PMID:25683117
• American Journal of Medical Genetics Part A • 2018 • Cole-Carpenter syndrome in a patient from Thailand. PMID:30063094
• Journal of Medical Genetics • 2018 • P4HB recurrent missense mutation causing Cole-Carpenter syndrome. PMID:29263160
• 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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