Point mutations at the carboxy terminus of the human dystrophin gene: implications for an association with mental retardation in DMD patients

Abstract

Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutations in the human dystrophin gene. About two-thirds of DMD/BMD patients exhibit gross rearrangements in the gene whereas the mutations in the remaining one third are thought to be point mutations or minor structural lesions. By means of various progressive PCR-based techniques hitherto a number of point mutations has been described that in most cases should cause premature translational termination. These data indicate a particular functional importance for the C-termlnal region of dystrophin and consequently for its gene products Dp 71 and Dp 116. To screen for mlcroheterogeneities in this gene region we applied PCR-SSCP analysis to exons 60 – 79 of twenty-six DMD/BMD patients without detectable deletions. The study identified seven point mutations and one intron polymorphism. Six point mutations, found in DMD patients, should cause premature translational termination. One point mutation, identified in a BMD patient, results in an amino acid exchange. Five of the DMD patients bearing a point mutation are mentally retarded suggesting that a disruption of the translational reading frame in the C-terminal region is associated with this clinical finding in DMD cases. Therefore our data raise the possibility, that Dp 71 and/or Dp 116, the C-termlnal translational products of dystrophin, may be causally involved in cases of mental retardation that are associated with DMD.