Genetic and physical mapping of the myotonic dystrophy locus on human chromosome 19q13.3.

Abstract

The cloning of the myotonic dystrophy (DM) was accomplished in a three part research plan: (1) the characterization of the DNA excision repair cross complementation (ERCC1) gene region by genetic and physical mapping to determine the location of the DM gene relative to this locus, (2) the undertaking of a chromosome walk from the ERCC1 region toward the DM gene to define a minimal area that is to contain the DM locus, and (3) characterization of the essential region containing the DM locus for CpG islands and DM associated abnormalities. Further work done in our laboratory and by others have shown the DM associated allelic expansion to be due to the amplification of a trinucleotide repeat, CTG. This repeat was mapped to the 3$\sp\prime$ untranslated region of a gene which based on sequence homology comparisons encodes a putative serine-threonine protein kinase. This is not unlike the allelic expansion found in fragile X syndrome that is due to an amplification of a CGG trinucleotide repeat mapping to the 5$\sp\prime$ untranslated region of a gene designated FMR-1. The size of the CTG repeats ascertained in 124 normal chromosomes was found to range from 5 to 30 with repeat numbers of 5 and 13 the most common. The repeat numbers in DM chromosomes was found to vary from a minimum of about 50 to over 2000. Only two out of 98 DM families did not show allelic expansion using Southern blot analysis or PCR protocols to ascertain the repeat numbers. These cases either have other mutations at or near this locus or they have another clinically similar disorder mapping elsewhere in the genome. In summary, it is evident from work presented in this thesis that the DM locus has been cloned and that the DM mutation has been identified. (Abstract shortened by UMI.)