An Unstable Triplet Repeat in a Gene Related to Myotonic Muscular Dystrophy

Abstract

Synthetic oligonucleotides containing GC-rich triplet sequences were used in a scanning strategy to identify unstable genetic sequences at the myotonic dystrophy (DM) locus. A highly polymorphic GCT repeat was identified and found to be unstable, with an increased number of repeats occurring in DM patients. In the case of severe congenital DM, the paternal triplet allele was inherited unaltered while the maternal, DM-associated allele was unstable. These studies suggest that the mutational mechanism leading to DM is triplet amplification, similar to that occurring in the fragile X syndrome. The triplet repeat sequence is within a gene (to be referred to as myotonin-protein kinase), which has a sequence similar to protein kinases.

Genetics of Human Sleep Behavioral Phenotypes

“…Identifying the specific genetic variants responsible for sleep phenotypes will promise to broaden our understanding of sleep regulation in similar ways essential components of many diseases were revealed (Fu et al, 1991(Fu et al, , 1992Karayiorgou et al, 1995;Ptacek et al, 1991;Xu, Hsu, Stark, Karayiorgou, & Gogos, 2013). From the forward genetics point of view, this approach also resembles how the circadian mechanisms were originally delineated in flies and mice (Konopka & Benzer, 1971;Vitaterna et al, 1994).…”

Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases

“…Fragile X syndrome has been found to be caused by expansion of a CGG trinucleotide repeat in the 5'-UTR Oberle et al, 1991;Yu et al, 1991;Verkerk et al, 1991), while expansion of a CTG trinucleotide repeat in the T-UTR has been identified in myotonic dystrophy (Mahadevan et al, 1992;Fu et al, 1992;Brook et al, 1992). Expansion of an intronic GAA trinucleotide repeat has recently been identified in Friedreich's ataxia (Campuzano et al, 1996).…”

“…Friedreich's ataxia is an autosomal recessive neurodegenerative disorder characterized by ata• decreased or absent tendon reflexes and impairment of deep sensation (Campuzano et al, 1996). Myotonic dystrophy is an autosomal dominant disease affecting multiple organs including muscle and other tissues (Mahadevan et al, 1992;Fu et al, 1992;Brook et al, 1992). Clinical features of myotonic dystrophy are characterized by myotonia (prolonged contraction of muscle after voluntary contraction or percussion), weakness in distal muscles, cataract, frontal baldness and endocrine abnormalities.…”

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

“…602668) is caused by a (CCTG) n expansion in intron 1 of the CNBP (CCHC-type zinc-finger nucleic acid-binding protein gene, formerly ZNF9, MIM *116955) on chromosome 3q21. [4][5][6][7][8] For DM1, disease severity and age of onset show a strong correlation with the size of the repeat expansion, which is associated with the phenomenon of anticipation. 9 Variation in repeat size and in somatic repeat expansion in different tissues can partly explain the variability of the phenotype.…”