Effect of Myotonic Dystrophy Trinucleotide Repeat Expansion on DMPK Transcription and Processing

Krahe, Ralf; Ashizawa, Tetsuo; Abbruzzese, Claudia; Roeder, Elizabeth; Carango, Paul; Giacanelli, Manlio; Funanage, Vicky L.; Siciliano, Michael J.

doi:10.1006/geno.1995.1099

Cited by 134 publications

(75 citation statements)

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“…This RNA was not polyadenylated, appeared as aggregates in the nucleus, and was not physically associated with the mutant copy of the gene (DNA). In parallel, both we (16) and Krahe et al (46) showed that the DM kinase RNA containing the expansion mu-tation was present at high levels in patient muscle, but that the mutant transcripts were poorly polyadenylated, and were presumably not available for translation. In addition, we found that the normal RNA transcripts from the normal copy of the gene were similarly poorly polyadenylated, suggesting a trans effect of the mutant RNA on RNA metabolism (16).…”

Section: Discussionmentioning

confidence: 53%

RNA metabolism in myotonic dystrophy: patient muscle shows decreased insulin receptor RNA and protein consistent with abnormal insulin resistance.

Morrone¹,

Pegoraro²,

Angelini³

et al. 1997

J. Clin. Invest.

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Myotonic dystrophy is a dominantly inherited clinically variable multisystemic disorder, and has been found to be caused by heterozygosity for a trinucleotide repeat expansion mutation in the 3 Ј untranslated region of a protein kinase gene (DM kinase). The mechanisms by which the expanded repeat in DNA results in a dominant biochemical defect and the varied clinical phenotype, is not known. We have recently proposed a model where disease pathogenesis may occur at the RNA level in myotonic dystrophy: the mutant DM kinase RNA with the expansion mutation may disrupt cellular RNA metabolism in some general manner, as evidenced by defects in RNA processing of the normal DM kinase gene in heterozygous patients (dominant negative RNA mutation). Here we further test this hypothesis by measuring RNA metabolism of other genes in patient muscle biopsies (nine adult onset myotonic dystrophy patients, two congenital muscular dystrophy patients, four normal controls, and four myopathic controls). We focused on the insulin receptor gene because of the documented insulin resistance of DM patients. We show that there is a significant decrease in insulin receptor RNA in both total RNA and RNA polyA ϩ pools relative to normal and myopathic control muscles ( P Ͻ 0.002), measured relative to both dystrophin RNA and muscle sodium channel RNA. We also show reductions in insulin receptor protein. Our results reinforce the concept of a generalized RNA metabolism defect in myotonic dystrophy, and offer a possible molecular mechanism for the increased insulin resistance observed in many myotonic dystrophy patients. (

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Section: Discussionmentioning

confidence: 53%

RNA metabolism in myotonic dystrophy: patient muscle shows decreased insulin receptor RNA and protein consistent with abnormal insulin resistance.

Morrone¹,

Pegoraro²,

Angelini³

et al. 1997

J. Clin. Invest.

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“…For comparative RT-PCR and TaqMan 5Ј nuclease assays, both BAALC and the housekeeping gene GPI (glucose phosphate isomerase; ref. 13) were coamplified in the same tube. The TaqMan assays were carried out for each sample in triplicates.…”

Section: Methodsmentioning

confidence: 99%

BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia

Tanner

Austin

Leone

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

131

123

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The molecular basis of human leukemia is heterogeneous. Cytogenetic findings are increasingly associated with molecular abnormalities, some of which are being understood at the functional level. Specific therapies can be developed based on such knowledge. To search for new genes in the acute leukemias, we performed a representational difference analysis. We describe a human gene in chromosome 8q22.3, BAALC (brain and acute leukemia, cytoplasmic), that is highly conserved among mammals but evidently absent from lower organisms. We characterized BAALC on the genomic level and investigated its expression pattern in human and mouse, as well as its complex splicing behavior. In vitro studies of the protein showing its subcellular localization suggest a function in the cytoskeleton network. Two isoforms are specifically expressed in neuroectoderm-derived tissues, but not in tumors or cancer cell lines of nonneural tissue origin. We show that blasts from a subset of patients with acute leukemia greatly overexpress eight different BAALC transcripts, resulting in five protein isoforms. Among patients with acute myeloid leukemia, those overexpressing BAALC show distinctly poor prognosis, pointing to a key role of the BAALC products in leukemia. Our data suggest that BAALC is a gene implicated in both neuroectodermal and hematopoietic cell functions.

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“…It is now generally accepted that the ancestral mutation(s) arose on a predisposing haplotype(s), with a mid-size (CTG) repeat allele being the most ancient chromosome (Imbert et al 1993;Mahadevan et al 1993;Rubinsztein et al 1994;Neville et al 1994;Krahe et al 1995aKrahe et al , 1995bKrahe et al , 1995cGoldman et al 1995;Deka et al 1996;Tishkoff et al 1998), and that DM1 could arise due to recurrent expansions occurring on a predisposing allelic form of the normal gene (Imbert et al 1993), with such a predisposition occurring in the (CTG) repeat itself.…”

Section: Discussionmentioning

confidence: 99%

Patients with primary cataract as a genetic pool of DMPK protomutation

et al. 2006

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Myotonic dystrophy 1 (DM1) is known to diminish reproductive fitness in its severe form. Since no de novo mutations are known for this disease, it has the tendency to becomeextinct from a population. To explain the preservation of DM1 in a population, a hypothesis that a pool of subjects for the mutated gene exists in the apparently healthy (non-DM1) population was tested. In order to determine the (CTG) repeat number, PCR was performed in 274 patients found to have primary cataract of adult onset who showed no DM1 symptoms, and were not related to DM1 patients. In four cataract patients (1.46%; 95% CI 0.5-3.7), a protomutation in the myotonin protein kinase gene was found which might lead to a complete mutation after transmission through the next generations. The number of (CTG) repeats in the remaining 270 cataract patients did not differ significantly from the control subjects in terms of the distribution of larger [(CTG)n ‡ 19] versus smaller [(CTG)n < 19] alleles. We consider the primary cataract patients to be the pool of DMPK protomutation from which DM1 mutation is maintained in the population.

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Effect of Myotonic Dystrophy Trinucleotide Repeat Expansion on DMPK Transcription and Processing

Cited by 134 publications

References 0 publications

RNA metabolism in myotonic dystrophy: patient muscle shows decreased insulin receptor RNA and protein consistent with abnormal insulin resistance.

RNA metabolism in myotonic dystrophy: patient muscle shows decreased insulin receptor RNA and protein consistent with abnormal insulin resistance.

BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia

Patients with primary cataract as a genetic pool of DMPK protomutation

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