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. et al. (2010) 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, 19(8), pp. 1399-1412. (doi:10.1093/hmg/ddq015)

Full text not currently available from Enlighten.

Abstract

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 [~]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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Monckton, Professor Darren and Braida, Mrs Claudia and Adam, Mrs Berit and Stefanatos, Miss Rhoda
Authors: Braida, C., Stefanatos, R.K.A., Adam, B., Mahajan, N., Smeets, H.J.M., Niel, F., Goizet, C., Arveiler, B., Koenig, M., Lagier-Tourenne, C., Mandel, J.-L., Faber, C.G., de Die-Smulders, C.E.M., Spaans, F., and Monckton, D.G.
Subjects:Q Science > QH Natural history > QH426 Genetics
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Human Molecular Genetics
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:15 January 2010

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
322401CTG repeat instability in Myotonic Dystrophy: Understanding the mechanism(s) of instability towards therapeutic approachesDarren MoncktonAssociation Francaise Contre Les Myopathies (AFM)under 8292RI MOLECULAR CELL & SYSTEMS BIOLOGY
330311Myotonic Dystrophy Research DonationDarren MoncktonMyotonic Dystrophy Support Group (MDSG)UNSPECIFIEDRI MOLECULAR CELL & SYSTEMS BIOLOGY
301161Determining the Function of D-SIX4, a Drosophila Homologue of Mammalian SIX5Darren MoncktonMuscular Dystrophy Campaign (MDCAM)RA3/614/1RI MOLECULAR CELL & SYSTEMS BIOLOGY