A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients |
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| Institution: | 1. Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica;2. Escuela de Medicina, Universidad de Costa Rica, San José, Costa Rica;3. Centro de Investigación en Neurociencias, Universidad de Costa Rica, San José, Costa Rica;4. Escuela de Nutrición, Universidad de Costa Rica, San José, Costa Rica;5. Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom;1. Radboud Institute for Molecular Life Sciences, Department of Cell Biology, Radboud University Medical Center, Geert Grooteplein 28, 6525 GA, Nijmegen, the Netherlands;2. Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK;3. Inserm UMR 1163, 75015 Paris, France;4. Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, 75270 Paris, France;5. UPMC Université Paris 06, Inserm UMRS974, CNRS FRE3617, Center for Research in Myology, Sorbonne Universités, 75252 Paris, France;1. Centre de référence maladies neuromusculaires, CHU Henri-Mondor, 51, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil, France;2. Inserm UMRS1138, team22, centre de recherche des cordeliers, 15, rue de l’École de Médecine, 75006 Paris, France;3. Institut universitaire de recherche clinique, CHU de Montpellier, 191, avenue du Doyen-Gaston-Giraud, 34090 Montpellier, France;4. Centre de référence maladies neuromusculaires Paris-Est, institut de myologie, hôpital Pitié-Salpêtrière, 47-83, boulevard de l’Hôpital, 75013 Paris, France;1. Department of Psychiatry, School of Medicine, Kyungpook National University, Daegu, South Korea;2. Department of Neurology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, South Korea;1. University of Oxford Medical School, Medical Sciences Division, University of Oxford, Oxford OX3 9DU, UK;2. Department of Physiology, Anatomy and Genetics, Oxford OX1 3QX, UK;3. Department of Paediatrics, University of Oxford, Oxford OX1 3QX, UK;4. MDUK Oxford Neuromuscular Centre, UK;1. Program of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada;2. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada;3. Department of Microbiology & Immunology, Dalhousie University, Nova Scotia, Canada;4. Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA;5. Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA;6. University of New Mexico Cancer Center,University of New Mexico School of Medicine, Albuquerque, NM 87131, USA |
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| Abstract: | Somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 is age-dependent, tissue-specific and expansion-biased, contributing toward the tissue-specificity and progressive nature of the symptoms. Previously, using regression modelling of repeat instability we showed that variation in the rate of somatic expansion in blood DNA contributes toward variation in age of onset, directly implicating somatic expansion in the disease pathway. Here, we confirm these results using a larger more genetically homogenous Costa Rican DM1 cohort (p < 0.001). Interestingly, we also provide evidence that supports subtle sex-dependent differences in repeat length-dependent age at onset and somatic mutational dynamics. Previously, we demonstrated that variation in the rate of somatic expansion was a heritable quantitative trait. Given the important role that DNA mismatch repair genes play in mediating expansions in mouse models, we tested for modifier gene effects with 13 DNA mismatch gene polymorphisms (one each in MSH2, PMS2, MSH6 and MLH1; and nine in MSH3). After correcting for allele length and age effects, we identified three polymorphisms in MSH3 that were associated with variation in somatic instability: Rs26279 (p = 0.003); Rs1677658 (p = 0.009); and Rs10168 (p = 0.031). However, only the association with Rs26279 remained significant after multiple testing correction. Although we revealed a statistically significant association between Rs26279 and somatic instability, we did not detect an association with the age at onset. Individuals with the A/A genotype for Rs26279 tended to show a greater propensity to expand the CTG repeat than other genotypes. Interestingly, this SNP results in an amino acid change in the critical ATPase domain of MSH3 and is potentially functionally dimorphic. These data suggest that MSH3 is a key player in generating somatic variation in DM1 patients and further highlight MSH3 as a potential therapeutic target. |
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| Keywords: | Myotonic dystrophy Somatic mosaicism Modifier gene DNA mismatch repair Simple sequence repeat Trinucleotide repeat |
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