title: 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: Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada. Electronic address: frauch@shriners.mcgill.ca.
authors: Frank
authors: F
authors: Rauch
authors: Department of Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal, QC H3A 1B1, Canada.
authors: Somayyeh
authors: S
authors: Fahiminiya
authors: Department of Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal, QC H3A 1B1, Canada.
authors: Jacek
authors: J
authors: Majewski
authors: Department of Human Genetics, McGill University and Génome Québec Innovation Centre, Montréal, QC H3A 1B1, Canada.
authors: Jian
authors: J
authors: Carrot-Zhang
authors: Shriners Hospital for Children, Portland, OR 97239, USA.
authors: Sergei
authors: S
authors: Boudko
authors: Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada.
authors: Francis
authors: F
authors: Glorieux
authors: Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada.
authors: John S
authors: JS
authors: Mort
authors: Shriners Hospital for Children, Portland, OR 97239, USA.
authors: Hans-Peter
authors: HP
authors: Bächinger
authors: Shriners Hospital for Children, Montréal, QC H3G 1A6, Canada.
authors: Pierre
authors: P
authors: Moffatt
mesh_terms: D002675:Child, Preschool; D003398:Craniosynostoses / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics*; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010375:Pedigree; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D019704:Protein Disulfide-Isomerases / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D017422:Sequence Analysis, DNA
chemical_list: D011393:Procollagen-Proline Dioxygenase; C526497:P4HB protein, human; D019704:Protein Disulfide-Isomerases