Myotonic Dystrophy Type 2: Human Founder Haplotype and Evolutionary Conservation of the Repeat Tract

Abstract

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.

Colocalization of ribonuclear inclusions with muscle blind like-proteins in a family with myotonic dystrophy type 2 associated with a short CCTG expansion

“…As described by Liquori et al [11], alleles displaying an uninterrupted stretch of 20 CCTG can be valued as premutational. Indeed, the repeat that was found in patients 1 and 2 by cloning comprised 32 succeeding CCTG without interruption.…”

Myotonic dystrophy type 2 is rare in the Japanese population

“…The number of CCTG repeats is o30 in the normal allele, with interruptions by GCTG and/or TCTG motifs, and this allele is stably transmitted from one generation to the next. 1,3 However, in the expanded allele only the CCTG tract elongates and no GCTG and TCTG interruptions occur. The expanded ZNF9 allele is extremely unstable and the size is highly variable, ranging from 75 to 11 000 repeats, with a mean of 5000 CCTG repeats.…”

“…4 To date, DM2 mutations have been identified predominantly in European Caucasians. 3,5 Although a small number of DM2 mutations have been reported in non-European populations, including families in Morocco, Algeria, Lebanon, Afghanistan and Sri Lanka, 6,7 all reported that DM2 patients had been considered to originate from a single common founder because they shared an identical haplotype. 3,5,7 However, in 2008 we identified the first case of DM2 in an East-Asian population, in a Japanese patient with a disease haplotype distinct from that shared among Caucasians, indicating that DM2 exists in non-Caucasian populations and that there may have been separate founders.…”

“…Both the Finnish and Italian population are expected to be a relatively representative European population with regard to the DM2 mutation, because of a single European founder haplotype. 3,5,7 Genomic DNA was extracted from blood leukocytes or muscle biopsy samples according to the standard protocols. The CCTG repeat size was determined by PCR, using primers flanking the repeat.…”

“…The origin of most DM2 mutations is estimated to be 200-540 generations ago in Europe, and DM2 has since spread into several European populations. 3 The rarity of DM2 in East-Asian populations may be because of a lack of founder effects or extinction of DM2 by genetic drift or selective causes.…”