Insulin receptor splicing alteration in myotonic dystrophy type 2.

Myotonic dystrophy (DM) is caused by either an untranslated CTG expansion in the 3' untranslated region of the DMPK gene on chromosome 19 (dystrophia myotonica type 1 [DM1]), or an untranslated CCTG tetranucleotide repeat expansion in intron 1 of the ZNF9 gene on chromosome 3 (dystrophia myotonica type 2 [DM2]). RNA-binding proteins adhere to transcripts of the repeat expansions that accumulate in the nucleus, and a trans-dominant dysregulation of pre-mRNA alternative splicing has been demonstrated for several genes. In muscle from patients with DM1, altered insulin-receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the DM phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of the disease. We now demonstrate that comparable splicing abnormalities occur in DM2 muscle prior to the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions.

[1]  E. Nanba,et al.  [Myotonic dystrophy]. , 2005, Nihon rinsho. Japanese journal of clinical medicine.

[2]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[3]  W. Hauswirth,et al.  A Muscleblind Knockout Model for Myotonic Dystrophy , 2003, Science.

[4]  L. Ranum,et al.  Myotonic dystrophy: Clinical and molecular parallels between myotonic dystrophy type 1 and type 2 , 2002, Current neurology and neuroscience reports.

[5]  S. Cannon,et al.  Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. , 2002, Molecular cell.

[6]  T. Cooper,et al.  Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. , 2002, Molecular cell.

[7]  C. Junien,et al.  Defective satellite cells in congenital myotonic dystrophy. , 2001, Human molecular genetics.

[8]  T. Cooper,et al.  Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy , 2001, Nature Genetics.

[9]  S. Naylor,et al.  Myotonic Dystrophy Type 2 Caused by a CCTG Expansion in Intron 1 of ZNF9 , 2001, Science.

[10]  이현철,et al.  Homeostasis Model Assessment법을 이용한 인슐린저항성 평가의 한계 , 2000 .

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

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

[13]  M. Laakso,et al.  How good a marker is insulin level for insulin resistance? , 1993, American journal of epidemiology.

[14]  David E. Housman,et al.  Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member , 1992, Cell.

[15]  J. Flier,et al.  Tissue-specific expression of two alternatively spliced insulin receptor mRNAs in man. , 1989, Molecular endocrinology.

[16]  G. Bell,et al.  Alternative splicing of human insulin receptor messenger RNA. , 1989, Biochemical and biophysical research communications.

[17]  R. Griggs,et al.  Muscle insulin resistance in myotonic dystrophy , 1980, Neurology.

[18]  R. Griggs,et al.  Decreased insulin sensitivity of forearm muscle in myotonic dystrophy. , 1978, The Journal of clinical investigation.