Letter abstract
Nature Genetics 40, 443 - 448 (2008)
Published online: 9 March 2008 | Corrected online: 26 June 2008 | doi:10.1038/ng.97
There is a Corrigendum (July 2008) associated with this Letter.
There is a Corrigendum (July 2008) associated with this Letter.
There is a Corrigendum (July 2008) associated with this Letter.
There is a Corrigendum (July 2008) associated with this Letter.
Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome
Carmen C Leitch1, Norann A Zaghloul1, Erica E Davis1, Corinne Stoetzel2, Anna Diaz-Font3, Suzanne Rix3, Majid Alfadhel4, Richard Alan Lewis5, Wafaa Eyaid4, Eyal Banin6, Helene Dollfus2, Philip L Beales3, Jose L Badano1,7 & Nicholas Katsanis1
Meckel-Gruber syndrome (MKS) is a genetically heterogeneous, neonatally lethal malformation and the most common form of syndromic neural tube defect (NTD). To date, several MKS-associated genes have been identified whose protein products affect ciliary function1, 2, 3, 4, 5. Here we show that mutations in MKS1, MKS3 and CEP290 (also known as NPHP6) either can cause Bardet-Biedl syndrome (BBS) or may have a potential epistatic effect on mutations in known BBS-associated loci. Five of six families with both MKS1 and BBS mutations manifested seizures, a feature that is not a typical component of either syndrome. Functional studies in zebrafish showed that mks1 is necessary for gastrulation movements and that it interacts genetically with known bbs genes. Similarly, we found two families with missense or splice mutations in MKS3, in one of which the affected individual also bears a homozygous nonsense mutation in CEP290 that is likely to truncate the C terminus of the protein. These data extend the genetic stratification of ciliopathies and suggest that BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum.
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733. N Broadway, Baltimore, Maryland 21205, USA.
- Laboratoire de Génétique Médicale EA 3439 équipe Avenir/INSERM, Faculté de Médecine de Strasbourg, Université Louis Pasteur, 11 rue Humann, 67085 Strasbourg, France.
- Molecular Medicine Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
- Department of Pediatrics, King Fahad Hospital, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
- Departments of Ophthalmology, Molecular and Human Genetics, Pediatrics, and Medicine, Baylor College of Medicine, Smith Tower, 6550 Fannin, Suite 1501, Houston, Texas 77030, USA.
- Department of Ophthalmology, Hadassah–Hebrew University Hospital, P.O. Box 12000, 91120 Jerusalem, Israel.
- Institut Pasteur de Montevideo, Calle Mataojo 2020, CP11400 Montevideo, Uruguay.
Correspondence to: Nicholas Katsanis1 e-mail: katsanis@jhmi.edu
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