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Original Article
P4HB recurrent missense mutation causing Cole-Carpenter syndrome
  1. Meena Balasubramanian1,2,
  2. Raja Padidela3,
  3. Rebecca C Pollitt4,5,
  4. Nicholas J Bishop4,
  5. M Zulf Mughal3,
  6. Amaka C Offiah4,
  7. Bart E Wagner6,
  8. Janine McCaughey7,
  9. David J Stephens7
  1. 1 Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK
  2. 2 Highly Specialised Service for Severe, Complex and Atypical OI Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK
  3. 3 Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  4. 4 Academic Unit of Child Health, University of Sheffield, Sheffield, UK
  5. 5 Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK
  6. 6 Department of Histopathology, Royal Hallamshire Hospital, Sheffield, UK
  7. 7 Cell Biology Laboratories, School of Biochemistry, University of Bristol, Bristol, UK
  1. Correspondence to Dr Meena Balasubramanian, Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield S10 2TH, UK; meena.balasubramanian{at}


Background Cole-Carpenter syndrome (CCS) is commonly classified as a rare Osteogenesis Imperfecta (OI) disorder. This was following the description of two unrelated patients with very similar phenotypes who were subsequently shown to have a heterozygous missense mutation in P4HB.

Objectives Here, we report a 3-year old female patient with severe OI who on exome sequencing was found to carry the same missense mutation in P4HB as reported in the original cohort. We discuss the genetic heterogeneity of CCS and underlying mechanism of P4HB in collagen production.

Methods We undertook detailed clinical, radiological and molecular phenotyping in addition, to analysis of collagen in cultured fibroblasts and electron microscopic examination in the patient reported here.

Results The clinical phenotype appears consistent in patients reported so far but interestingly, there also appears to be a definitive phenotypic clue (crumpling metadiaphyseal fractures of the long tubular bones with metaphyseal sclerosis which are findings that are uncommon in OI) to the underlying genotype (P4HB variant).

Discussion P4HB (Prolyl 4-hydroxylase, betasubunit) encodes for PDI (Protein Disulfide isomerase) and in cells, in its tetrameric form, catalyses formation of 4-hydroxyproline in collagen. The recurrent variant in P4HB, c.1178A>G, p.Tyr393Cys, sits in the C-terminal reactive centre and is said to interfere with disulphide isomerase function of the C-terminal reactive centre. P4HB catalyses the hydroxylation of proline residues within the X-Pro-Gly repeats in the procollagen helical domain. Given the inter-dependence of extracellular matrix (ECM) components in assembly of a functional matrix, our data suggest that it is the organisation and assembly of the functional ECM that is perturbed rather than the secretion of collagen type I per se.

Conclusions We provide additional evidence of P4HB as a cause of a specific form of OI-CCS and expand on response to treatment with bisphosphonates in this rare disorder.

  • osteogenesis imperfecta
  • p4hb
  • collagen processing
  • recurrent mutation
  • skeletal dysplasia

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  • Contributors All authors contributed to preparation and critical review of manuscript; MB: study design, writing up the manuscript, recruitment of patient and phenotyping; RP, NJB and MZM: patient phenotyping; ACO: radiology input; RCP: exome sequencing; BEW: EM studies; JM and DJS: functional studies on patient fibroblasts.

  • Funding This research was supported by The Sheffield Children’s Hospital Charity (TCHC) grant number CA15001 and a postgraduate scholarship from the University of Bristol to JM.

  • Competing interests None declared.

  • Ethics approval Yorkshire and Humber REC.

  • Provenance and peer review Not commissioned; externally peer reviewed.