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

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

Author Jenkins, Dagan Google Scholar
Seelow, Dominik Google Scholar
Jehee, Fernanda S. Google Scholar
Perlyn, Chad A. Google Scholar
Alonso, Luis Garcia Autor UNIFESP Google Scholar
Bueno, Daniela F. Google Scholar
Donnai, Dian Google Scholar
Josifiova, Dragana Google Scholar
Mathijssen, Irene M. J. Google Scholar
Morton, Jenny E. V. Google Scholar
Orstavik, Karen Helene Google Scholar
Sweeney, Elizabeth Google Scholar
Wall, Steven A. Google Scholar
Marsh, Jeffrey L. Google Scholar
Nurnberg, Peter Google Scholar
Passos-Bueno, Maria Rita Google Scholar
Wilkie, Andrew O. M. Google Scholar
Institution Univ Oxford
Oxford Radcliffe Hosp
Univ Cologne
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Universidade Estadual de Campinas (UNICAMP)
Washington Univ
St Johns Mercy Med Ctr
Univ Manchester
Guys Hosp
Erasmus MC
Womens Hosp Med Ctr
Univ Oslo
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 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.
Language English
Date 2007-06-01
Published in American Journal of Human Genetics. Chicago: Univ Chicago Press, v. 80, n. 6, p. 1162-1170, 2007.
ISSN 0002-9297 (Sherpa/Romeo, impact factor)
Publisher Univ Chicago Press
Extent 1162-1170
Origin http://dx.doi.org/10.1086/518047
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000246553800014
URI http://repositorio.unifesp.br/handle/11600/29763

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