title: Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect.
abstract: Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.
authors.affiliation: Section of Cancer Genetics, Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Bachinski
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meola
authors.forename: Valeria
authors.initials: V
authors.lastname: Sansone
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bassez
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.forename: Richard T
authors.initials: RT
authors.lastname: Moxley
authors.forename: Peter S
authors.initials: PS
authors.lastname: Harper
authors.forename: Mark T
authors.initials: MT
authors.lastname: Rogers
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann-Horn
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieser
authors.forename: Josep
authors.initials: J
authors.lastname: Gamez
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Armand
authors.initials: A
authors.lastname: Bottani
authors.forename: Andre
authors.initials: A
authors.lastname: Kohler
authors.forename: Mark D
authors.initials: MD
authors.lastname: Shriver
authors.forename: Riitta
authors.initials: R
authors.lastname: Sallinen
authors.forename: Maija
authors.initials: M
authors.lastname: Wessman
authors.forename: Shanxiang
authors.initials: S
authors.lastname: Zhang
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.forename: Ralf
authors.initials: R
authors.lastname: Krahe
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D005060:Europe / Q000208:ethnology; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009223:Myotonic Dystrophy / Q000145:classification / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D014481:United States