(mentions CMT) Variant CCG and GGC repeats within the CTG expansion dramatically

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Hum Mol Genet. 2010 Jan 15

Variant CCG and GGC repeats within the CTG expansion dramatically modify

mutational dynamics and likely contribute toward unusual symptoms in some

myotonic dystrophy type 1 patients.

Braida C, Stefanatos RK, Adam B, Mahajan N, Smeets HJ, Niel F, Koenig M,

Lagier-Tourenne C, Mandel JL, Faber CG, de Die-Smulders CE, Spaans F, Monckton

DG.

Molecular Genetics, Faculty of Biomedical and Life Sciences, University of

Glasgow, University Avenue, Glasgow G12 8QQ, UK.

Myotonic dystrophy type 1 (DM1) is one of the most variable inherited human

disorders. It is characterized by the involvement of multiple tissues and is

caused by the expansion of a highly unstable CTG repeat. Variation in disease

severity is partially accounted for by the number of CTG repeats inherited.

However, the basis of the variable tissue-specific symptoms is unknown. We have

determined that an unusual Dutch family co-segregating DM1, Charcot-Marie-Tooth

neuropathy, encephalopathic attacks and early hearing loss, carries a complex

variant repeat at the DM1 locus. The mutation comprises an expanded CTG tract at

the 5'-end and a complex array of CTG repeats interspersed with multiple GGC and

CCG repeats at the 3'-end. The complex variant repeat tract at the 3'-end of the

array is relatively stable in both blood DNA and the maternal germ line, whilst

the 5'-CTG tract remains genetically unstable and prone to expansion.

Surprisingly though, even the pure 5'-CTG tract is more stable in blood DNA and

the maternal germ line than archetypal DM1 alleles of a similar size. Complex

variant repeats were also identified at the 3'-end of the CTG array of

approximately 3-4% of unrelated DM1 patients. The observed polarity and the

stabilizing effect of the variant repeats implicate a cis-acting modifier of

mutational dynamics in the 3'-flanking DNA. The presence of such variant repeats

very likely contributes toward the unusual symptoms in the Dutch family and

additional symptomatic variation in DM1 via affects on both RNA toxicity and

somatic instability.