Cause of Proximal Myotonic Myopathy: DM2

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Myotonic dystrophy (DM) is one of a class of triplet repeat diseases. In these diseases, a short stretch of DNA that is normally repeated several times undergoes dynamic or expansion mutation. During DNA replication, the cellular machinery slips and generates extra copies of the triplet repeat. The disease occurs once the expansion exceeds a threshold number of repeats. Other triplet diseases include Huntington’s disease, spinal and bulbar muscular atrophy (SBMA), and fragile X syndrome.

DM2 (also known as proximal myotonic myopathy [PROMM]) is caused by an expanded and unstable (CCTG)n tetranucleotide repeat in the first intron of the zinc finger 9 (Znf9, also known as Cnbp) gene on chromosome 3q21.

Unaffected individuals typically have less than 75 repeats. Once the repeat number excees 75, the expanded sequence becomes unstable and slippage is more frequent. Affected individuals can have been 75 and 11,000 copies of the repeat sequence.

The figure below presents a visual explanation of the cause of DM2.



The repeat structure in DM2 is more complex than the triplet repeat seen in DM1. The normal repeat structure is approximately 10-20 repeats of a complex motif that is 104 to 176 nucleotides long ((TG)12-26(TCTG)7-12(CCTG)3-9(g/tCTG)0-4(CCTG)4-15 ).

Individuals with 22-33 uninterrupted CCTG repeats are said to carry a pre-mutation. These individuals are asymptomatic and are unlikely ever to show symptoms. However, these repeats are unstable and very likely to expand during meiosis. As a result, such individuals are at risk of having affected children.

The minimum pathogenic length of the expanded region appears to be 75 uninterrupted CCTG repeats. Repeat counts can increase to over 11,000 in affected individuals, with a mean repeat length of ~5000 repeats. The expanded region has been shown to display an even greater instability than the DM1 mutation.

Unlike DM1, the length of the DM2 repeated DNA expansion does not appear to correlate significantly with the age of onset or severity of disease symptoms. 

Somatic mosaicism
Tissues in affected individuals can have unstable expanded regions. Repeat count can increase significantly over time in certain tissues, but no increase may be seen in others. The resulting dramatic somatic mosaicism can lead to diagnostic and treatment challenges. The presence of somatic mosaicism helps explain, in part, the variability seen between individuals, including members of the same family, who appear to have similar repeat counts.


Genetic testing
Genetic testing is available for DM2 using standard DNA diagnostic protocols to determine definitively whether or not an individual has DM2. Since the size of the repeats may be thousands of base pairs in length, the repeat expansion is too large for PCR testing in some cases. In those instances, southern blot techniques are used for diagnosis.

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