title: Somatic instability of the expanded CTG triplet repeat in myotonic dystrophy type 1 is a heritable quantitative trait and modifier of disease severity.
abstract: Deciphering the contribution of genetic instability in somatic cells is critical to our understanding of many human disorders. Myotonic dystrophy type 1 (DM1) is one such disorder that is caused by the expansion of a CTG repeat that shows extremely high levels of somatic instability. This somatic instability has compromised attempts to measure intergenerational repeat dynamics and infer genotype-phenotype relationships. Using single-molecule PCR, we have characterized more than 17 000 de novo somatic mutations from a large cohort of DM1 patients. These data reveal that the estimated progenitor allele length is the major modifier of age of onset. We find no evidence for a threshold above which repeat length does not contribute toward age at onset, suggesting pathogenesis is not constrained to a simple molecular switch such as nuclear retention of the DMPK transcript or haploinsufficiency for DMPK and/or SIX5. Importantly, we also show that age at onset is further modified by the level of somatic instability; patients in whom the repeat expands more rapidly, develop the symptoms earlier. These data establish a primary role for somatic instability in DM1 severity, further highlighting it as a therapeutic target. In addition, we show that the level of instability is highly heritable, implying a role for individual-specific trans-acting genetic modifiers. Identifying these trans-acting genetic modifiers will facilitate the formulation of novel therapies that curtail the accumulation of somatic expansions and may provide clues to the role these factors play in the development of cancer, aging and inherited disease in the general population.
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Fernando
authors.initials: F
authors.lastname: Morales
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Couto
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Higham
authors.forename: Grant
authors.initials: G
authors.lastname: Hogg
authors.forename: Patricia
authors.initials: P
authors.lastname: Cuenca
authors.forename: Claudia
authors.initials: C
authors.lastname: Braida
authors.forename: Richard H
authors.initials: RH
authors.lastname: Wilson
authors.forename: Berit
authors.initials: B
authors.lastname: Adam
authors.forename: Gerardo
authors.initials: G
authors.lastname: del Valle
authors.forename: Roberto
authors.initials: R
authors.lastname: Brian
authors.forename: Mauricio
authors.initials: M
authors.lastname: Sittenfeld
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ashizawa
authors.forename: Alison
authors.initials: A
authors.lastname: Wilcox
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Wilcox
authors.forename: Darren G
authors.initials: DG
authors.lastname: Monckton
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D056726:Genetic Association Studies; D042822:Genomic Instability; D057895:Haploinsufficiency / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009223:Myotonic Dystrophy / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D019655:Quantitative Trait, Heritable; D019680:Trinucleotide Repeat Expansion
chemical_list: C585517:DMPK protein, human; D018398:Homeodomain Proteins; C106687:SIX5 protein, human; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases