The present study was performed to evaluate the association between the PPARalpha polymorphism L162V and the presence of dyslipidemia and/or atherosclerotic disease in patients with DM-2 in comparison with nondiabetic controls.
Characterization of a single nucleotide polymorphism in the ZNF9 gene and analysis of association with myotonic dystrophy type II (DM2) in the Italian population.
Myotonic dystrophy type 2 (DM2) is a dominantly inherited disorder with multisystemic clinical features, caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene.
The mutation responsible for DM1 is a CTG repeat in the 3' UTR of the dystrophia myotonica protein kinase gene (DMPK) on chromosome 19q13.3, while DM2 is caused by an unstable CCTG expansion in intron 1 of the zinc finger protein 9 gene (ZNF9) on chromosome 3q21.3.
The mutation responsible for DM1 is a CTG repeat in the 3' UTR of the dystrophia myotonica protein kinase gene (DMPK) on chromosome 19q13.3, while DM2 is caused by an unstable CCTG expansion in intron 1 of the zinc finger protein 9 gene (ZNF9) on chromosome 3q21.3.
Protein tyrosine phosphatase-1B (PTP-1B) dephosphorylates various receptor protein kinases in vitro, including the beta subunit of the insulin receptor, therefore representing a potential candidate to be involved in the polygenic pathogenesis of DM-2.
The presence of the Pro387Leu variant of the PTP-1B gene was investigated using polymerase chain reaction (PCR) restriction fragment-length polymorphism in 402 subjects with DM-2 (231 men, 171 women, age 63.1 +/- 10.8 years, BMI 28.7 +/- 5.1 kg m(-2)) and in 434 normoglycemic age- and sex-matched control subjects (248 men, 186 women, age 64.4 +/- 6.5 years, BMI 26.5 +/- 3.7 kg m(-2)).
The presence of the +62G-->A polymorphism of the resistin gene was investigated using polymerase chain reaction-restriction fragment length polymorphism in 384 subjects with DM-2 [224 men, 160 women, age 63.4 +/- 10.6 years, body mass index (BMI) 28.7 +/- 5.1 kg m(-2)] and in 434 nondiabetic age- and sex-matched control subjects (248 men, 186 women, age 64.4 +/- 6.5 years, BMI 26.5 +/- 3.7 kg m(-2)).
To address the issue of ZNF9 role in DM2, we have analyzed the effects of (CCTG)n expansion on ZNF9 expression in lymphoblastoid cell lines (n=4) from DM2 patients.
The identification and characterization of RNA-binding proteins that interact with expanded CUG repeats and the discovery that a similar transcribed but untranslated CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2) have uncovered a new type of mechanism in which microsatellite expansion mutations cause disease through an RNA gain-of-function mechanism.
Since prior work demonstrated that CTG*CAG and GAA*TTC triplet repeats (responsible for DM1 and Friedreich's ataxia, respectively) can expand by genetic recombination, we investigated the capacity of the DM2 tetranucleotide repeats to also expand during this process.
The expansions of long repeating tracts of CTG.CAG, CCTG.CAGG, and GAA.TTC are integral to the etiology of myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), and Friedreich's ataxia (FRDA).
This review discusses RNA pathogenesis in DM1 and DM2 and evidence that similar mechanisms may play a role in a growing number of dominant noncoding expansion disorders, including fragile X tremor ataxia syndrome (FXTAS), spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12, and Huntington's disease-like 2 (HDL2).
This review discusses RNA pathogenesis in DM1 and DM2 and evidence that similar mechanisms may play a role in a growing number of dominant noncoding expansion disorders, including fragile X tremor ataxia syndrome (FXTAS), spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12, and Huntington's disease-like 2 (HDL2).
These disorders are distinguished from myotonic dystrophy type 1 (DM-1), the more recently described proximal myotonic myopathy/myotonic dystrophy type 2 (PROMM/DM-2), and proximal myotonic dystrophy (a variant of DM-2) by characteristic clinical features, lack of abnormal nucleotide repeat expansions in the DM-1 and DM-2 genes, lack of cataracts and endocrine disturbances, and absence of significant histopathology in the muscle biopsy.
The mutant RNA transcripts of DM1 and DM2 aberrantly affect the splicing of the same target RNAs, such as chloride channel 1 (ClC-1) and insulin receptor (INSR), resulting in their shared myotonia and insulin resistance.
The mutant RNA transcripts of DM1 and DM2 aberrantly affect the splicing of the same target RNAs, such as chloride channel 1 (ClC-1) and insulin receptor (INSR), resulting in their shared myotonia and insulin resistance.
The results of our immunofluorescence study indicate that, among patients examined, MBNL1 nuclear sequestration in protein foci is a molecular pathology marker of DM1 and DM2 patients where ribonuclear inclusions of transcripts with expanded CUG/CCUG repeats are also present.