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Carpenter syndrome is a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. Using homozygosity mapping, we found linkage to chromosome 6p12.1-q12 and, in 15 independent families, identified five different mutations (four truncating and one missense) in RAB23, which encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling. In 10 patients, the disease was caused by homozygosity for the same nonsense mutation, L145X, that resides on a common haplotype, indicative of a founder effect in patients of northern European descent. Surprisingly, nonsense mutations of Rab23 in open brain mice cause recessive embryonic lethality with neural-tube defects, suggesting a species difference in the requirement for RAB23 during early development. The discovery of RAB23 mutations in patients with Carpenter syndrome implicates HH signaling in cranial-suture biogenesis--an unexpected finding, given that craniosynostosis is not usually associated with mutations of other HH-pathway components--and provides a new molecular target for studies of obesity.

Original publication

DOI

10.1086/518047

Type

Journal article

Journal

Am J Hum Genet

Publication Date

06/2007

Volume

80

Pages

1162 - 1170

Keywords

Acrocephalosyndactylia, Chromosome Mapping, Chromosomes, Human, Pair 6, Cranial Sutures, Genes, Recessive, Genetic Linkage, Hedgehog Proteins, Humans, Mutation, Obesity, Signal Transduction, Syndrome, rab GTP-Binding Proteins