Copyright © 2003 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 73, Issue 4, 849-862, 1 October 2003
doi:10.1086/378720
Myotonic Dystrophy Type 2: Human Founder Haplotype and Evolutionary Conservation of the Repeat Tract
Christina L. Liquori1, 2, Yoshio Ikeda1, 2, Marcy Weatherspoon1, 2, Kenneth Ricker4, Benedikt G.H. Schoser5, Joline C. Dalton1, 2, John W. Day1, 3 and Laura P.W. Ranum1, 2, 
, 
1 Institute of Human Genetics, Department of, Cell Biology, and Development, Minneapolis
2 Department of Genetics, Cell Biology, and Development, Minneapolis
3 Department of Neurology, University of Minnesota, Minneapolis
4 Department of Neurology, University of Würzburg, Würzburg, Germany
5 Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University, Munich
Address for correspondence and reprints: Dr. Laura P. W. Ranum, Department of Genetics, Cell Biology and Development and the Institute of Human Genetics, MMC 206, 420 Delaware Street SE, University of Minnesota, Minneapolis, MN 55455Abstract
Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19 (DM1) or 3 (DM2). In 2001, we demonstrated that DM2 is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. To investigate the ancestral origins of the DM2 expansion, we compared haplotypes for 71 families with genetically confirmed DM2, using 19 short tandem repeat markers that we developed that flank the repeat tract. All of the families are white, with the majority of Northern European/German descent and a single family from Afghanistan. Several conserved haplotypes spanning >700 kb appear to converge into a single haplotype near the repeat tract. The common interval that is shared by all families with DM2 immediately flanks the repeat, extending up to 216 kb telomeric and 119 kb centromeric of the CCTG expansion. The DM2 repeat tract contains the complex repeat motif (TG)n(TCTG)n(CCTG)n. The CCTG portion of the repeat tract is interrupted on normal alleles, but, as in other expansion disorders, these interruptions are lost on affected alleles. We examined haplotypes of 228 control chromosomes and identified a potential premutation allele with an uninterrupted (CCTG)20 on a haplotype that was identical to the most common affected haplotype. Our data suggest that the predominant Northern European ancestry of families with DM2 resulted from a common founder and that the loss of interruptions within the CCTG portion of the repeat tract may predispose alleles to further expansion. To gain insight into possible function of the repeat tract, we looked for evolutionary conservation. The complex repeat motif and flanking sequences within intron 1 are conserved among human, chimpanzee, gorilla, mouse, and rat, suggesting a conserved biological function.
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