title: MBNL1 gene variants as modifiers of disease severity in myotonic dystrophy type 1.
abstract: Myotonic dystrophy type 1 (DM1) is a multisystemic autosomal dominant disorder characterized by a highly variable phenotype and caused by an unstable CTG repeat expansion in the 3' untranslated region of the dystrophia 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 Muscleblind-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 phenotype, 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.
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Huin
authors.forename: Francis
authors.initials: F
authors.lastname: Vasseur
authors.forename: Susanna
authors.initials: S
authors.lastname: Schraen-Maschke
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Dhaenens
authors.forename: Patrick
authors.initials: P
authors.lastname: Devos
authors.forename: Kathy
authors.initials: K
authors.lastname: Dupont
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lacour
authors.forename: Hélène
authors.initials: H
authors.lastname: Hofmann-Radvanyi
authors.forename: Bernard
authors.initials: B
authors.lastname: Sablonnière
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009223:Myotonic Dystrophy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D012044:Regression Analysis; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D055815:Young Adult
chemical_list: C493663:MBNL1 protein, human; D016601:RNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases