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

Linda L. Bachinski, Bjarne Udd, Giovanni Meola, Valeria Sansone, Guillaume Bassez, Bruno Eymard, Charles A. Thornton, Richard T. Moxley, Peter S. Harper, Mark T. Rogers, Karin Jurkat-Rott, Frank Lehmann-Horn, Thomas Wieser, Josep Gamez, Carmen Navarro, Armand Bottani, Andre Kohler, Mark Shriver, Riitta Sallinen, Maija WessmanShanxiang Zhang, Fred A. Wright, Ralf Krahe

Research output: Contribution to journalArticle

104 Citations (Scopus)

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 micro satellite 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 ∼200-540 generations.

Original languageEnglish (US)
Pages (from-to)835-848
Number of pages14
JournalAmerican Journal of Human Genetics
Volume73
Issue number4
DOIs
StatePublished - Oct 1 2003

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Founder Effect
Myotonic Dystrophy
Haplotypes
Mutation
Muscular Dystrophies
Myotonia
Linkage Disequilibrium
3' Untranslated Regions
Introns
Population
Single Nucleotide Polymorphism
Chromosomes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Bachinski, Linda L. ; Udd, Bjarne ; Meola, Giovanni ; Sansone, Valeria ; Bassez, Guillaume ; Eymard, Bruno ; Thornton, Charles A. ; Moxley, Richard T. ; Harper, Peter S. ; Rogers, Mark T. ; Jurkat-Rott, Karin ; Lehmann-Horn, Frank ; Wieser, Thomas ; Gamez, Josep ; Navarro, Carmen ; Bottani, Armand ; Kohler, Andre ; Shriver, Mark ; Sallinen, Riitta ; Wessman, Maija ; Zhang, Shanxiang ; Wright, Fred A. ; Krahe, Ralf. / 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. In: American Journal of Human Genetics. 2003 ; Vol. 73, No. 4. pp. 835-848.
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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 micro satellite 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 ∼200-540 generations.",
author = "Bachinski, {Linda L.} and Bjarne Udd and Giovanni Meola and Valeria Sansone and Guillaume Bassez and Bruno Eymard and Thornton, {Charles A.} and Moxley, {Richard T.} and Harper, {Peter S.} and Rogers, {Mark T.} and Karin Jurkat-Rott and Frank Lehmann-Horn and Thomas Wieser and Josep Gamez and Carmen Navarro and Armand Bottani and Andre Kohler and Mark Shriver and Riitta Sallinen and Maija Wessman and Shanxiang Zhang and Wright, {Fred A.} and Ralf Krahe",
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Bachinski, LL, Udd, B, Meola, G, Sansone, V, Bassez, G, Eymard, B, Thornton, CA, Moxley, RT, Harper, PS, Rogers, MT, Jurkat-Rott, K, Lehmann-Horn, F, Wieser, T, Gamez, J, Navarro, C, Bottani, A, Kohler, A, Shriver, M, Sallinen, R, Wessman, M, Zhang, S, Wright, FA & Krahe, R 2003, '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', American Journal of Human Genetics, vol. 73, no. 4, pp. 835-848. https://doi.org/10.1086/378566

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. / Bachinski, Linda L.; Udd, Bjarne; Meola, Giovanni; Sansone, Valeria; Bassez, Guillaume; Eymard, Bruno; Thornton, Charles A.; Moxley, Richard T.; Harper, Peter S.; Rogers, Mark T.; Jurkat-Rott, Karin; Lehmann-Horn, Frank; Wieser, Thomas; Gamez, Josep; Navarro, Carmen; Bottani, Armand; Kohler, Andre; Shriver, Mark; Sallinen, Riitta; Wessman, Maija; Zhang, Shanxiang; Wright, Fred A.; Krahe, Ralf.

In: American Journal of Human Genetics, Vol. 73, No. 4, 01.10.2003, p. 835-848.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Confirmation of the Type 2 Myotonic Dystrophy (CCTG)n Expansion Mutation in Patients with Proximal Myotonic Myopathy/Proximal Myotonic Dystrophy of Different European Origins

T2 - A Single Shared Haplotype Indicates an Ancestral Founder Effect

AU - Bachinski, Linda L.

AU - Udd, Bjarne

AU - Meola, Giovanni

AU - Sansone, Valeria

AU - Bassez, Guillaume

AU - Eymard, Bruno

AU - Thornton, Charles A.

AU - Moxley, Richard T.

AU - Harper, Peter S.

AU - Rogers, Mark T.

AU - Jurkat-Rott, Karin

AU - Lehmann-Horn, Frank

AU - Wieser, Thomas

AU - Gamez, Josep

AU - Navarro, Carmen

AU - Bottani, Armand

AU - Kohler, Andre

AU - Shriver, Mark

AU - Sallinen, Riitta

AU - Wessman, Maija

AU - Zhang, Shanxiang

AU - Wright, Fred A.

AU - Krahe, Ralf

PY - 2003/10/1

Y1 - 2003/10/1

N2 - 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 micro satellite 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 ∼200-540 generations.

AB - 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 micro satellite 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 ∼200-540 generations.

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