RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
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.
Jenkins
Dagan
D
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Seelow
Dominik
D
Jehee
Fernanda S
FS
Perlyn
Chad A
CA
Alonso
Luis G
LG
Bueno
Daniela F
DF
Donnai
Dian
D
Josifova
Dragana
D
Josifiova
Dragana
D
Mathijssen
Irene M J
IM
Morton
Jenny E V
JE
Orstavik
Karen Helene
KH
Sweeney
Elizabeth
E
Wall
Steven A
SA
Marsh
Jeffrey L
JL
Nurnberg
Peter
P
Passos-Bueno
Maria Rita
MR
Wilkie
Andrew O M
AO
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*
D053823:Hedgehog Proteins; C486614:RAB23 protein, human; D020691:rab GTP-Binding Proteins