POINT MUTATIONS AT THE CARBOXY-TERMINUS OF THE HUMAN DYSTROPHIN GENE - IMPLICATIONS FOR AN ASSOCIATION WITH MENTAL-RETARDATION IN DMD PATIENTS

Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutat ions in the human dystrophin gene. About two-thirds of DMD/BMD patient s exhibit gross rearrangements in the gene whereas the mutations in th e remaining one third are thought to be point mutations or minor struc tural lesions. By means of various progressive PCR-based techniques hi therto a number of point mutations has been described that in most cas es should cause premature translational termination. These data indica te a particular functional importance for the C-terminal region of dys trophin and consequently for its gene products Dp 71 and Dp 116. To sc reen for microheterogeneities in this gene region we applied PCR-SSCP analysis to exons 60-79 of twenty-six DMD/BMD patients without detecta ble deletions. The study identified seven point mutations and one intr on polymorphism. Six point mutations, found in DMD patients, should ca use premature translational termination. One point mutation, identifie d in a BMD patient, results in an amino acid exchange. Five of the DMD patients bearing a point mutation are mentally retarded suggesting th at a disruption of the translational reading frame in the C-terminal r egion is associated with this clinical finding in DMD cases. Therefore our data raise the possibility, that Dp 71 and/or Dp 116, the C-termi nal translational products of dystrophin, may be causally involved in cases of mental retardation that are associated with DMD.