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

Am J Hum Genet. 2007 Jun;80(6):1162-70. doi: 10.1086/518047. Epub 2007 Apr 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrocephalosyndactylia / genetics*
  • Chromosome Mapping
  • Chromosomes, Human, Pair 6
  • Cranial Sutures / growth & development*
  • Genes, Recessive
  • Genetic Linkage
  • Hedgehog Proteins / physiology*
  • Humans
  • Mutation*
  • Obesity*
  • Signal Transduction
  • Syndrome
  • rab GTP-Binding Proteins / genetics*


  • Hedgehog Proteins
  • RAB23 protein, human
  • rab GTP-Binding Proteins