RAB23 Mutations in Carpenter Syndrome Imply an Unexpected Role for Hedgehog Signaling in Cranial-Suture Development and Obesity
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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.
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These mutations demonstrate pathogenic roles for steroid metabolism and hedgehog (or possibly Wnt) signalling in cranial suture development, both of which are poorly understood.
“These mutations demonstrate pathogenic roles for steroid metabolism and hedgehog (or possibly Wnt) signalling in cranial suture development, both of which are at present poorly understood.”
From Craniosynostosis (2011) · cites this paper as [36]
Antley-Bixler syndrome (features include disordered sex development and radio-humeral synostosis; POR mutation) and Carpenter syndrome (polysyndactyly; RAB23 mutation) are recessive disorders, whereas most genetically determined craniosynostosis is dominant.
“Whereas most genetically determined craniosynostosis is characterised by dominant inheritance, Antley-Bixler syndrome (features include disordered sex development and radio-humeral synostosis; mutation in POR encoding cytochrome P450 oxidoreductase) 35 and Carpenter syndrome (with polysyndactyly; mutation in RAB23 encoding RAB23, member of RAS oncogene family) 36 are recessive disorders.”
From Craniosynostosis (2011) · cites this paper as [36]
Additional convergence in sCS is seen in the Hedgehog pathway, involving ALX4, IHH, and RAB23, and in the RAS/MAPK cascade, given the association of sCS with RASopathies and variants in BRAF, PTPN11, and MAP4K4.
“Additional convergence is seen in the Hedgehog pathway, involving ALX4, IHH, and RAB23 [46, 72, 77], and in the RAS/MAPK cascade, given the association of sCS with RASopathies and variants in BRAF, PTPN11, and MAP4K4 [61, 112, 122].”
From Genetics versus environment in the pathophysiology of sagittal synostosis (2026) · cites this paper as [72]
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Genetic Basis of Human Congenital Heart DiseasePreprint
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Consequences of Rab GTPase dysfunction in genetic or acquired human diseases
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Cranial sutures: a multidisciplinary review
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Rab and Arf Proteins in Genetic Diseases
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The role of the small GTP ase Rab31 in cancer
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FGFR-Related Craniosynostosis Syndromes
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The Evi5 family in cellular physiology and pathology
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Planar Cell Polarity Effector Proteins Inturned and Fuzzy Form a Rab23 GEF Complex
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Rab GTPases, Membrane Trafficking and Diseases
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- Authors
- Jenkins, D., Seelow, D., Jehee, F. S., Perlyn, C. A., Alonso, L. G., Bueno, D. F., Donnai, D., Josifiova, D., Mathijssen, I. M. J., Morton, J. E. V., Helene Ørstavik, K., Sweeney, E., Wall, S. A., Marsh, J. L., Nürnberg, P., Rita Passos-Bueno, M., & Wilkie, A. O. M.
- Affiliations
- Guy's Hospital (GB)
- University of Cologne (DE)
- Universidade de São Paulo (BR)
- Universidade Federal de São Paulo (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- University of Manchester (GB)
- Erasmus MC (NL)
- Birmingham Women's Hospital (GB)
- Liverpool Women's Hospital (GB)
- National Health Service (GB)
- Corresponding author
- Wilkie, Andrew O.M.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 80
- Issue
- 6
- Pages
- 1162-1170
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1867103
- OpenAlex
- W2074166336
- Cited by
- 276
- References
- 39
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 13 · 2023: 13 · 2022: 12 · 2021: 15 · 2020: 13 · 2019: 8 · 2018: 14 · 2017: 18 · 2016: 11 · 2015: 13 · 2014: 18 · 2013: 14 · 2012: 20
- FWCI
- 9.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Americanae (AECID Library) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Carpenter syndrome, Rab23, Hedgehog signaling, craniosynostosis, obesity, founder effect, homozygosity mapping, nonsense mutation, neural tube defects, autosomal recessive inheritance, polysyndactyly, cardiac defects, vesicle trafficking
- MeSH terms
- Acrocephalosyndactylia, Chromosome Mapping, Chromosomes, Human, Pair 6, Cranial Sutures, Genes, Recessive, Humans, Genetic Linkage, Mutation, Obesity, Syndrome, Signal Transduction, rab GTP-Binding Proteins, Hedgehog Proteins
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