Molecular Genetics of Dystrophinopathies

Abstract

Abstract The term dystrophinopathies includes a spectrum of muscle diseases caused by mutations in the dystrophin ( DMD ) gene. The commonest mutations are intragenic deletions (65% of cases) and duplications (10%); the remaining 25% are small mutations (missense, nonsense, frameshifting and indels). Atypical mutations (deep intronic, or in 5′/3′ untranslated regions) account for no more than 1%. The functional consequences of mutations are related to the maintenance of the open reading frame, though exceptions to the rule are known. A precise molecular characterisation of dystrophin mutations is nowadays mandatory for the inclusion of patients in therapeutic trials, as the antisense‐mediated targeted exon skipping or the stop codon reversion uses gentamycin and ataluren drugs. Understanding the complexity of the dystrophin gene regulation has provided outstanding information about muscle functions, sarcolemma architecture and signalling circuits, muscle metabolism and other basic science mechanisms. Key Concepts: The dystrophin gene ( DMD ) is one of the largest disease genes in the human genome. Dystrophin deficiency accounts for different allelic conditions: Duchenne and Becker muscular dystrophies (DMD/BMD) are X‐linked recessive hereditary myopathies in which the skeletal muscle is affected with a nonreversible, age‐dependent degeneration. Allelic dystrophin mutations can also give rise to isolated cardiac involvement, or X‐linked dilated cardiomyopathy (XLDC). The commonest mutational event in the dystrophin gene is represented by intragenic deletions accounting for 65% of dystrophin mutations. Intragenic duplications account for 10% of all mutations and small mutations represent 25%. The functional consequences of all mutation types are mainly related to the maintenance of the open reading frame: ‘inframe’ mutations result in a shorter but partially functional dystrophin and are associated with BMD. Frame‐shift mutations are related to the absence of protein production and a DMD phenotype. The fine genetic characterisation of dystrophin mutations has become mandatory for making patients eligible for novel personalised trials.