RAB23 mutations in carpenter syndrome imply an unexpected role for Hedgehog signaling in cranial-suture development and obesity Article

Jenkins, D, Seelow, D, Jehee, FS et al. (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. 10.1086/518047

cited authors

  • Jenkins, D; Seelow, D; Jehee, FS; Perlyn, CA; Alonso, LG; Bueno, DF; Donnai, D; Josifiova, D; Mathijssen, IMJ; Morton, JEV; Ørstavik, KH; Sweeney, E; Wall, SA; Marsh, JL; Nürnberg, P; Passos-Bueno, MR; Wilkie, AOM

authors

abstract

  • 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. © 2007 by The American Society of Human Genetics. All rights reserved.

publication date

  • January 1, 2007

published in

Digital Object Identifier (DOI)

start page

  • 1162

end page

  • 1170

volume

  • 80

issue

  • 6