Stable and Unstable Trinucleotide CTG Repeat Alleles in Myotonic Dystrophy Locus
Myotonic dystrophy (DM), an autosomal dominant hereditary disease that predominantly affecting the central nervous and muscular systems (1) and is caused by a CTG- repeat expansion located in the 3'- untranslated region of the protein kinase (DMPK) gene in locus of human chromosome 19q13.3. The normal copy number ranges from 5 to 30 repeats and expansions of the CTG repeats up to several thousand show a positive correlation between the length of the CTG repeat and the severity of clinical symptoms. To date, the mechanism by which the DM expansion mutation leads to the diverse clinical phenotype of DM remains unknown (2).Recently, fast and efficient methods as triplet repeat primed PCR and XL CTG PCR for DNA analysis of number and length of CTG repeats (3,4) in DMPK locus were introduced.The analyse of the lengths of the CTG repeat in the normal population shown the highly variable allele frequency distribution of CTG repeat alleles at the DMPK locus in 60 unrelated healthy individuals from the South Moravia region with determination of the most frequent 5 CTG allele in the normal range. As it shown, alleles from the interval 5 to 29 were not unstable and conform to normal Mendelian inheritance in non DM pedigrees (5). DNA diagnosis for direct CTG repeat expansion in a DM family with increased severity of disease in successive generations was provided. In examinedDM family proband was patient - girl in the age of 8, normal karyotype 46, XX , with diagnosis of a myotonic syndrome. The clinical picture of the disease was characterised by progressive weakness and wasting of muscles, by cataract and mask-like face. Determined genotype of the patient was (CTG) n 5 /expanded allele, her mother carriared normal allele 13 and the second allele with 100 CTG repeat. The grandmother was not examined but her sister, clinically affected was determined as a carrier of the long expand CTG allele. In this DM family the maternal origin instability , the increase of CTG repeat size and worse phenotype in the consecutive generation was proved.
(1) Harper P. S. (1989) Myotonic Dystrophy, 2nd ed. (London:W.B. Asounders Co.)
Falk M., Silhanova E1, Grochova I. and Vojtiskova, M.
Department of Human Genetics,