title: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
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.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Dagan
authors.initials: D
authors.lastname: Jenkins
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: Jehee
authors.forename: Chad A
authors.initials: CA
authors.lastname: Perlyn
authors.forename: Luis G
authors.initials: LG
authors.lastname: Alonso
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Bueno
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.forename: Dragana
authors.initials: D
authors.lastname: Josifova
authors.forename: Dragana
authors.initials: D
authors.lastname: Josifiova
authors.forename: Irene M J
authors.initials: IM
authors.lastname: Mathijssen
authors.forename: Jenny E V
authors.initials: JE
authors.lastname: Morton
authors.forename: Karen Helene
authors.initials: KH
authors.lastname: Orstavik
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sweeney
authors.forename: Steven A
authors.initials: SA
authors.lastname: Wall
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Marsh
authors.forename: Peter
authors.initials: P
authors.lastname: Nurnberg
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics*; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D003393:Cranial Sutures / Q000254:growth & development*; D005808:Genes, Recessive; D008040:Genetic Linkage; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D009154:Mutation; D009765:Obesity; D015398:Signal Transduction; D013577:Syndrome; D020691:rab GTP-Binding Proteins / Q000235:genetics*
chemical_list: D053823:Hedgehog Proteins; C486614:RAB23 protein, human; D020691:rab GTP-Binding Proteins