Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of ZNF9

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3′ untranslated region of the dystrophia myotonica–protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean ∼5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.

[1]  A. Wilkie.  Faculty Opinions recommendation of Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. , 2001 .

[2]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[3]  D. Haussler,et al.  A physical map of the human genome , 2001, Nature.

[4]  K. Suzuki,et al.  The CUG-binding protein binds specifically to UG dinucleotide repeats in a yeast three-hybrid system. , 2000, Biochemical and biophysical research communications.

[5]  Takanori Yamagata,et al.  Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10 , 2000, Nature Genetics.

[6]  S. Tapscott.  Deconstructing Myotonic Dystrophy , 2000, Science.

[7]  R. J. White,et al.  Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. , 2000, Science.

[8]  B. Byrne,et al.  Recruitment of human muscleblind proteins to (CUG)n expansions associated with myotonic dystrophy , 2000, The EMBO journal.

[9]  A. Ziegler,et al.  Proximal myotonic myopathy , 2000, Neurology.

[10]  Y. Chai,et al.  Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts , 2000, Nature Genetics.

[11]  John I. Clark,et al.  Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy , 2000, Nature Genetics.

[12]  J. Brook,et al.  Myotonic dystrophy is associated with a reduced level of RNA from the DMWD allele adjacent to the expanded repeat. , 1999, Human molecular genetics.

[13]  T. Bird,et al.  An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8) , 1999, Nature Genetics.

[14]  L. Ranum,et al.  Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2) , 1999, Neuromuscular Disorders.

[15]  K. Toyka,et al.  Linkage of proximal myotonic myopathy to chromosome 3q , 1999, Neurology.

[16]  L. Timchenko,et al.  Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. , 1999, Human molecular genetics.

[17]  J. Ashby.  References and Notes , 1999 .

[18]  B. Wieringa,et al.  Expanding complexity in myotonic dystrophy , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[19]  L. Pellizzoni,et al.  Involvement of the Xenopus laevis Ro60 autoantigen in the alternative interaction of La and CNBP proteins with the 5'UTR of L4 ribosomal protein mRNA. , 1998, Journal of molecular biology.

[20]  T. Cooper,et al.  Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. , 1998, Science.

[21]  L. Ranum,et al.  Genetic mapping of a second myotonic dystrophy locus , 1998, Nature Genetics.

[22]  S. Tapscott,et al.  Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP , 1997, Nature Genetics.

[23]  R. Moxley,et al.  Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene , 1997, Nature Genetics.

[24]  D. Housman,et al.  Expansion of a CUG trinucleotide repeat in the 3' untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Mandel,et al.  Transition from premutation to full mutation in fragile X syndrome is likely to be prezygotic. , 1997, Human molecular genetics.

[26]  L. Pellizzoni,et al.  Cellular nucleic acid binding protein binds a conserved region of the 5' UTR of Xenopus laevis ribosomal protein mRNAs. , 1997, Journal of molecular biology.

[27]  M. Swanson,et al.  Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. , 1996, Nucleic acids research.

[28]  D. Housman,et al.  Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy , 1996, Nature Genetics.

[29]  E. Morkin,et al.  Organization of the gene encoding cellular nucleic acid-binding protein. , 1995, Gene.

[30]  M. Siciliano,et al.  A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat. , 1995, Human molecular genetics.

[31]  S. Tapscott,et al.  Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Housman,et al.  Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues , 1995, The Journal of cell biology.

[33]  C. Richards,et al.  Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent. , 1995, American journal of human genetics.

[34]  R. Moxley,et al.  Proximal myotonic myopathy , 1994, Neurology.

[35]  M. Baiget,et al.  CTG trinucleotide repeat variability in identical twins with myotonic dystrophy , 1994, Annals of neurology.

[36]  R. Griggs,et al.  Myotonic dystrophy with no trinucleotide repeat expansion , 1994, Annals of neurology.

[37]  R. Gibbs,et al.  Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. , 1993, Science.

[38]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[39]  K. Svenson,et al.  Identification of a zinc finger protein that binds to the sterol regulatory element. , 1989, Science.

[40]  J. Veech,et al.  Vistas on Nematology: A Commemoration of the Twenty-fifth Anniversary of the Society of Nematologists. , 1987 .

[41]  J. Ott,et al.  Strategies for multilocus linkage analysis in humans. , 1984, Proceedings of the National Academy of Sciences of the United States of America.