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Title: RAB23 mutations in carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity
Authors: Jenkins, Dagan
Seelow, Dominik
Jehee, Fernanda S.
Perlyn, Chad A.
Alonso, Luis Garcia [UNIFESP]
Bueno, Daniela F.
Donnai, Dian
Josifiova, Dragana
Mathijssen, Irene M. J.
Morton, Jenny E. V.
Orstavik, Karen Helene
Sweeney, Elizabeth
Wall, Steven A.
Marsh, Jeffrey L.
Nurnberg, Peter
Passos-Bueno, Maria Rita
Wilkie, Andrew O. M.
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
Issue Date: 1-Jun-2007
Publisher: Univ Chicago Press
Citation: American Journal of Human Genetics. Chicago: Univ Chicago Press, v. 80, n. 6, p. 1162-1170, 2007.
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.
ISSN: 0002-9297
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