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Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis.

Original publication

DOI

10.1002/humu.21457

Type

Journal article

Journal

Hum Mutat

Publication Date

04/2011

Volume

32

Pages

E2069 - E2078

Keywords

Abnormalities, Multiple, Acrocephalosyndactylia, Base Sequence, Craniofacial Dysostosis, Female, Genotype, Homozygote, Humans, Male, Molecular Sequence Data, Mutation, Nervous System Malformations, Phenotype, RNA Stability, Syndrome, rab GTP-Binding Proteins