a universal mechanism ties genotype to phenotype in trinucleotide diseases一个通用的机制基因型在三核苷酸疾病表型的关系.pdfVIP

A Universal Mechanism Ties Genotype to Phenotype in Trinucleotide Diseases Shai Kaplan1,2, Shalev Itzkovitz1,3, Ehud Shapiro1,3* 1 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel, 2 Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel, 3 Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions; therefore, it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patient’s lifetime toward a pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype– phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntington disease with homozygous versus heterozygous mutation, and correlation of age of ons