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 cranialsuture 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.

Additional Metadata
Persistent URL dx.doi.org/10.1086/518047, hdl.handle.net/1765/35144
Journal American Journal of Human Genetics
Citation
Jenkins, D, Seelow, D, Jehee, F.S, Perlyn, C.A, Alonso, L.G, Bueno, D.F, … Wilkie, A.O.M. (2007). RAB23 mutations in carpenter syndrome imply an unexpected role for Hedgehog signaling in cranial-suture development and obesity. American Journal of Human Genetics, 80(6), 1162–1170. doi:10.1086/518047