Human Molecular Genetics Advance Access originally published online on September 20, 2008
Human Molecular Genetics 2008 17(24):4012-4021; doi:10.1093/hmg/ddn304
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WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon
1 Lebanese American University, School of Medicine, Chouran, Beirut 1102 2801, Lebanon, 2 Chronic Care Center, Hazmieh, Lebanon, 3 Division of Endocrinology, American University of Beirut, Bliss St, Beirut, Lebanon, 4 Centre National de Génotypage, Institut de Génomique, Commissariat à l’Énergie Atomique, 2 rue Gaston Crémieux, CP 5721, 91057 Evry Cedex, France, 5 Genetics of Infectious and Autoimmune Diseases, Institut Pasteur, 75015 Paris, France 6 Genetics of Diabetes, Inserm U730, Centre National de Génotypage, 2 rue Gaston Crémieux, CP 5721, 91057 Evry Cedex, France 7 Department of Ophthalmology, Hotel Dieu Hospital, Beirut, Lebanon
* To whom correspondence should be addressed. Genetics of Diabetes, Inserm U730, Centre National de Génotypage, 2 rue Gaston Crémieux, CP 5721, 91057 Evry Cedex, France. Tel: +33 160878330; Fax: +33 160878383; Email: cjulier{at}cng.fr
Received August 11, 2008; Revised September 8, 2008; Accepted September 16, 2008
Most cases of juvenile-onset diabetes (JOD) are diagnosed as type 1 diabetes (T1D), for which genetic studies conducted in outbred Caucasian populations support the concept of multifactorial inheritance. However, this view may be partly challenged in particular population settings. In view of the suggestive evidence for a high prevalence of Wolfram syndrome (WFS) in Lebanon, the phenotypic variability associated with WFS1 mutations, and the high consanguinity rate in Lebanon, we aimed to evaluate the contribution of WFS1 mutations as monogenic determinants to JOD in Lebanon. We performed a family-based genetic study, with linkage analysis followed by systematic mutation screening of WFS1 exons in all JOD probands. The study population consisted of an unbiased recruitment of all juvenile-onset insulin-dependent diabetic patients from a specialized diabetes pediatric clinic in Beirut, Lebanon. Homozygous or compound heterozygous WFS1 mutations were found in 22 of the 399 JOD probands (5.5%), resulting in WFS (17 probands) or in non-syndromic non-autoimmune diabetes mellitus (DM, five probands). These accounted for 12.1% (21/174) of probands in consanguineous families, compared with 0.4% (1/225) in non-consanguineous families. Of the 38 patients identified with homozygous or compound heterozygous WFS1 mutations, 11 (29%) had non-syndromic DM, all of whom carried a particular WFS1 mutation, WFS1LIB, encoding a protein with an extended C-terminal domain. This mutation resulted in a delayed onset or absence of extrapancreatic features. These results underscore the major impact of population-specific factors, such as population-specific mutations and founder effects, and family structure in the genetic determinism of JOD.