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From the Departments of Cancer Genetics (L.L.B., T.C., R.K.) and Molecular Genetics (L.S.R., M.J.S.), University of Texas M.D. Anderson Cancer Center, Houston, TX; Neurogenetics Program (T.S.), University of Tampere, Finland; Department of Neurology (B.U.), Tampere University Hospital, Finland; and Department of Anthropology (M.D.S.), Pennsylvania State University, University Park, PA.
Address correspondence and reprint requests to Dr. Ralf Krahe, Department of Cancer Genetics, Unit 1010, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009 rkrahe{at}mdanderson.org
Background: The myotonic dystrophies (DM1, DM2) are the most common adult muscle diseases and are characterized by multisystem involvement. DM1 has been described in diverse populations, whereas DM2 seems to occur primarily in European Caucasians. Both are caused by the expression of expanded microsatellite repeats. In DM1, there is a reservoir of premutation alleles; however, there have been no reported premutation alleles for DM2. The (CCTG)DM2 expansion is part of a complex polymorphic repeat tract of the form (TG)n(TCTG)n(CCTG)n(NCTG)n(CCTG)n. Expansions are as large as 40 kb, with the expanded (CCTG)n motif uninterrupted. Reported normal alleles have up to (CCTG)26 with one or more interruptions.
Methods: To identify and characterize potential DM2 premutation alleles, we cloned and sequenced 43 alleles from 23 individuals. Uninterrupted alleles were identified, and their instability was confirmed by small-pool PCR. We determined the genotype of a nearby single nucleotide polymorphism (rs1871922) known to be in linkage disequilibrium with the DM2 mutation.
Results: We identified three classes of large non-DM2 repeat alleles: 1) up to (CCTG)24 with two interruptions, 2) up to (CCTG)32 with up to four interruptions, and 3) uninterrupted (CCTG)22–33. Large non-DM2 alleles were more common in African Americans than in European Caucasians. Uninterrupted alleles were significantly more unstable than interrupted alleles (p = 10–4 to 10–7). Genotypes at rs1871922 were consistent with the hypothesis that all large alleles occur on the same haplotype as the DM2 expansion.
Conclusions: We conclude that unstable uninterrupted (CCTG)22-33 alleles represent a premutation allele pool for DM2 full mutations.
Abbreviations: AfrAm = African American; DM = myotonic dystrophy; EurCauc = European Caucasian; FISH = fluorescent in situ hybridization; MIM = Mendelian Inheritance in Man; NA = not available; SNP = single nucleotide polymorphism; SP-PCR = small-pool PCR.
Supplemental data at www.neurology.org
Editorial, page 484
e-Pub ahead of print on November 19, 2008, at www.neurology.org.
R.K. was supported in part by NIH grant AR48171 and MDA. B.U. was supported by Medicinska understödsföreningen Liv och Hälsa r.f., the Tampere University Hospital Research Funds, and the Folkhälsan Institute of Genetics.
Disclosure: The authors report no disclosures.
Received April 21, 2008. Accepted in final form July 22, 2008.
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 B. Schoser and T. Ashizawa How much expansion to be diseased?: Toward repeat size and myotonic dystrophy type 2 Neurology, February 10, 2009; 72(6): 484 - 485. [Full Text] [PDF]
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