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Published online before print November 19, 2008, doi:10.1212/01.wnl.0000333665.01888.33)
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Received April 21, 2008
Accepted July 22, 2008

Premutation allele pool in myotonic dystrophy type 2

L. L. Bachinski PhD, T. Czernuszewicz BS, L. S. Ramagli PhD, T. Suominen MS, M. D. Shriver PhD, B. Udd MD, PhD, M. J. Siciliano PhD, and R. Krahe PhD*

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.


* To whom correspondence should be addressed. E-mail: 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.


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