Cole-Carpenter syndrome is caused by a heterozygous missense mutation in P4HB.

Abstract

Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features. To identify the cause of Cole-Carpenter syndrome in the two individuals whose clinical results were presented in the original description of this disorder, we performed whole-exome sequencing of genomic DNA samples from both individuals. The two unrelated individuals had the same heterozygous missense mutation in exon 9 of P4HB (NM_000918.3: c.1178A>G [p.Tyr393Cys]), the gene that encodes protein disulfide isomerase (PDI). In one individual, the P4HB mutation had arisen de novo, whereas in the other the mutation was transmitted from the clinically unaffected father who was a mosaic carrier of the variant. The mutation was located in the C-terminal disulfide isomerase domain of PDI, sterically close to the enzymatic center, and affected disulfide isomerase activity in vitro. Skin fibroblasts showed signs of increased endoplasmic reticulum stress, but despite the reported importance of PDI for collagen type I production, the rate of collagen type I secretion appeared normal. In conclusion, Cole-Carpenter syndrome is caused by a specific de novo mutation in P4HB that impairs the disulfide isomerase activity of PDI.

• Authors: Frank Rauch, Somayyeh Fahiminiya, Jacek Majewski, Jian Carrot-Zhang, Sergei Boudko, Francis Glorieux, John S Mort, Hans-Peter Bächinger, Pierre Moffatt
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 96 Issue 3 Pg. 425-31 (Mar 05 2015) ISSN: 1537-6605 [Electronic] United States
• PMID: 25683117 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Procollagen-Proline Dioxygenase
• P4HB protein, human
• Protein Disulfide-Isomerases

Topics

• Child, Preschool
• Craniosynostoses (genetics)
• Eye Abnormalities (genetics)
• Female
• Gene Frequency
• Heterozygote
• Humans
• Hydrocephalus (genetics)
• Infant
• Male
• Mutation, Missense
• Osteogenesis Imperfecta (genetics)
• Pedigree
• Procollagen-Proline Dioxygenase (genetics, metabolism)
• Protein Conformation
• Protein Disulfide-Isomerases (genetics, metabolism)
• Protein Folding
• Sequence Analysis, DNA