Question

One of your friends has been diagnosed with myotonic dystrophy. Such genetic disorder runs in her family and the condition seems to be getting worse since it appeared generations ago. Provide genetic basis for such disorder and the explanation of why such condition gets worse over time.

Answer 1

Myotonic dystrophy is a type of adult muscle dystrophy characterized by prolonged muscle wasting and weakness. It is a progressive disorder where a patient has prolonged muscle contraction and cannot relax certain muscle after prolonged use. The patient also may have cataracts and cardiac conduction defects and sometimes even male infertility. There are two types: Type 1 and Type 2; caused by mutation is different genes. Type 2 has milder symptoms than Type 1. In Type 1, muscle weakness is in lower legs, hands, neck, and face. In Type 2, muscle weakness is in neck, shoulders, elbows, and hips. Childhood version of myotonic dystrophy called congenital myotonic dystrophy is of Type I.

Mutations in the DMPK (DM1 protein kinase) gene causes type 1, while type 2 is due to mutations in the CNBP (CCHC-type zinc finger nucleic acid binding protein) gene. DMPK protein is a serine threonine kinase that acts on myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. There are 5-38 copies of CTG trinucleotide repeats in the 3’ untranslated region of DMPK gene. Expansion of this motif to 50-500 copies causes type I myotonic dystrophy. As copy number increase of this motif, severity of the disease increases. Expansion of the repeat causes local chromosomal structure condensation that disrupts expression of genes in this region.

CNBP encodes for a nucleic acid protein that has seven zinc finger domains. CNBP is involved in cap-independent translation of mRNA for ornithine decarboxylase, and regulation of sterol-mediated transcription. The mutation is a CCTG expansion from <30 repeats to 75-11000 repeats in the first intron. However, it is unclear how DMPK and CNBP cause the disease. It is possible that DMPK is involved in communication with other cells and has a role in muscular movement.

These changes in both genes prevent functioning of muscle cells and cells in other tissues. The mutations are inherited in autosomal dominant pattern. Myotonic dystrophy is passed from one generation to next generation. However, passage to next generation will lead to symptoms being observed earlier in life, which get more severe. Such a phenomenon is called anticipation and is seen in both types of the diseases. Anticipation is caused by the increase in length of the repeats in DMPK gene. Mechanism of anticipation is type 2 is not known, as a longer unstable region in CNBP does not affect age of onset. The increase in length of the repeats in DMPK gene will occur during gametogenesis and is seen even in heterozygotes. Repeats length is higher when the transmission is from the father. The expansion of repeats increase in number over time and is responsible for increasing severity of symptoms over time.