ORIGINAL COMMUNICATION MBNL1 gene variants as modifiers of disease severity in myotonic dystrophy type 1 Vincent Huin • Francis Vasseur • Susanna Schraen-Maschke • Claire-Marie Dhaenens • Patrick Devos • Kathy Dupont • Nicolas Sergeant • Luc Bue ´e • Arnaud Lacour • He ´le `ne Hofmann-Radvanyi • Bernard Sablonnie `re Received: 21 August 2012 / Revised: 16 October 2012 / Accepted: 29 October 2012 Ó Springer-Verlag Berlin Heidelberg 2012 Abstract Myotonic dystrophy type 1 (DM1) is a multi- systemic autosomal dominant disorder characterized by a highly variable phenotype and caused by an unstable CTG repeat expansion in the 3 0 untranslated region of the dys- trophia myotonica protein kinase (DMPK) gene. Longer CTG repeat expansions often correlate with an anticipated age at onset and CTG repeat number may account for 45–60 % of the variance in disease severity. In order to search for candidate genes that could act as modifiers of disease severity, we studied the association between Mus- cleblind-like protein-1 (MBNL1) gene polymorphisms and the DM1 phenotype. In a group of 301 patients diagnosed with DM1 based on clinical symptoms, diagnosis was confirmed by molecular analysis of the DMPK gene. Patients were divided into four subtypes. The first subtype corresponded to asymptomatic patients or those with a mild phenotype, the second included those with a classic phe- notype, the third concerned childhood onset, and the fourth corresponded to the congenital form of DM1. Three SNPs located in the MBNL1 gene promoter, rs323622, rs17283597, and rs17433672, were studied. Case–control analysis revealed that allele frequencies for the latter two were significantly associated with DM1 (p = 0.037 and p = 0.020). Multivariate linear regression analysis using phenotype as the dependent variable demonstrated that the TT genotype of the third SNP, rs323622, was associated with a more severe phenotype (p = 0.0034) and accounted for 1.88 % of the variance in disease severity. We report the association of several genetic variants of the MBNL1 gene with DM1 or with the severity of the disease. Keywords Myotonic dystrophy Á Disease severity Á MBNL1 gene variants Introduction Myotonic dystrophy type 1 (DM1; MIM #160900) or Steinert’s disease, the most frequent inherited neuromus- cular disease in adults, is caused by the expansion of a dynamically unstable CTG trinucleotide repeat in the 3 0 -untranslated region (3 0 UTR) of the DMPK gene, located on chromosome 19q13.2 [1, 2]. Normal individuals have between 5 and 37 CTG repeats, while in patients, this number may reach from 50 to more than 4,000 [2]. Full penetrance alleles occur with repeat numbers greater than 50, and are nearly always associated with symptomatic disease. Patients with DM1 can be divided into four main V. Huin Á S. Schraen-Maschke Á C.-M. Dhaenens Á N. Sergeant Á L. Bue ´e Á B. Sablonnie `re (&) INSERM UMR837, Alzheimer and Tauopathies, University Lille-Nord de France, USDL, IMPRT, Jean-Pierre Aubert Research Center, Batiment Biserte, 1, Place de Verdun, 59045 Lille, France e-mail: bernard.sablonniere@inserm.fr F. Vasseur EA2694, Lille University Medical Center, Lille, France S. Schraen-Maschke Á C.-M. Dhaenens Á P. Devos Á K. Dupont Á B. Sablonnie `re Department of Molecular Biology, Lille University Medical Center, Lille, France A. Lacour Department of Clinical Neurology and Center for Rare Neuromuscular Diseases, Lille University Medical Center, Lille, France H. Hofmann-Radvanyi University Versailles-Saint Quentin en Yvelines, AP-HP, Biochemistry and Molecular Genetics Laboratory, Ho ˆpital Ambroise Pare ´, Boulogne, France 123 J Neurol DOI 10.1007/s00415-012-6740-y