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
Human Molecular Genetics. 2010-01-15; 19(8): 1399-1412
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1. Hum Mol Genet. 2010 Apr 15;19(8):1399-412. doi: 10.1093/hmg/ddq015. Epub 2010 Jan
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(1), Stefanatos RK, Adam B, Mahajan N, Smeets HJ, Niel F, Goizet C,
Arveiler B, Koenig M, Lagier-Tourenne C, Mandel JL, Faber CG, de Die-Smulders CE,
Spaans F, Monckton DG.
(1)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, although
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
PMID: 20080938 [Indexed for MEDLINE]