Clinical and genetic aspects of craniofrontonasal syndrome: Towards resolving a genetic paradox
Abstract
Craniofrontonasal syndrome (CFNS) is characterized by body asymmetry, midline defects, skeletal abnormalities, and dermatological abnormalities. It is a very peculiar X-linked syndrome because females are affected whereas male carriers show no or only mild abnormalities. Using a combination of positional approach and candidate gene strategy the EFNB1 gene in Xq12 was identified as the major causative gene of this condition. So far, 46 EFNB1 mutations have been detected in CFNS patients. The majority of the mutations lead to premature termination codons. Because the encoded protein ephrin-B1 is involved in migration of neural crest cells we propose that CFNS is a novel type of neurocrestopathy. The absent or mild phenotype in male carriers may be explained by the promiscuity of the ephrin ligand/receptor system. The more severe manifestation in females may be explained by cellular interference that is caused by the combination of ephrin ligand/receptor promiscuity and the consequences of random X inactivation in distinct cellular compartments.
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Causative mutations in EFNB1 confer loss of function and are diverse (whole gene deletions, intragenic nonsense and frameshifting and splice site mutations, and missense substitutions), providing an explanation for the paradoxical inheritance pattern.
“The identification of causative mutations in EFNB1, which confer loss of function and are correspondingly diverse (whole gene deletions, intragenic nonsense and frameshifting and splice site mutations, and missense substitutions; Figure 2d) (refs.31,32), has provided an explanation for the paradoxical inheritance pattern.”
From Craniosynostosis (2011) · cites this paper as [31]
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- Authors
- Wieacker, P., & Wieland, I.
- Affiliations
- Otto-von-Guericke-Universität Magdeburg (DE)
- Corresponding author
- Wieacker, Peter
- ORCID
- Wieland, Ilse
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2005-09
- Volume
- 86
- Issue
- 1-2
- Pages
- 110-116
- ISSN
- 1096-7192 (ISSN-L)
- OpenAlex
- W2023943103
- Cited by
- 69
- References
- 45
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 2 · 2015: 5 · 2014: 2 · 2013: 9 · 2012: 1
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- craniofrontonasal syndrome, ephrin-B1, X-linked inheritance, sex differences in phenotype, neural crest migration, X chromosome inactivation, premature stop codon, body asymmetry, midline defects, candidate gene identification
- MeSH terms
- Abnormalities, Multiple, Female, Humans, Male, Mutation, Nose, Skull, Syndrome, Signal Transduction, Receptors, Eph Family
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