Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy

Reddy, Sita; Smith, Daniel B.; Rich, Mark M.; Leferovich, John; Reilly, P.; Davis, Brigid M.; Tran, Khoa D.; Rayburn, Helen; Bronson, Roderick T.; Cros, Didier; Balice-Gordon, Rita J.; Housman, David E.

doi:10.1038/ng0796-325

Cited by 321 publications

(190 citation statements)

References 66 publications

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“…While all these data are consistent with haploinsufficiency of the cAMP kinase, it is difficult to understand how such mild changes in protein levels could result in the dramatic clinical variability seen in myotonic dystrophy patients. Moreover, transgenic mice that have no functional DM kinase (homozygous recessive, complete loss of function) show only a mild, late onset muscle phenotype, and share few of the other symptoms of the human disease (37,38).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…Although symptoms in skeletal muscle function are most prominent, DM also causes defects in nonmuscle cell types. The disease has been linked to a CTG triplet expansion in the 3'-untranslated exon of DM-kinase (Brook et al 1992;Fu et al 1992;Mahadevan et al 1992); but despite recent advances with mouse models (Jansen et al 1996;Reddy et al 1996), the substrate of DM-kinase and the pathway in which DM-kinase func tions are unknown. Based on the sequence similarities between human DM-kinase, C. elegans LET-502, and the other members of this kinase family shown in Figure 3, we propose that DM-kinase may act in a pathway similar to that shown in Figure 7, to influence cytoskeletal organization and cell shape.…”

Section: Possible Implications For Human Myotonic Dystrophymentioning

confidence: 99%

Caenorhabditis elegans LET-502 is related to Rho-binding kinases and human myotonic dystrophy kinase and interacts genetically with a homolog of the regulatory subunit of smooth muscle myosin phosphatase to affect cell shape.

Wißmann¹,

Ingles²,

McGhee³

et al. 1997

Genes Dev.

160

153

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We have identified two genes associated with the hypodermal cell shape changes that occur during elongation of the Caenorhabditis elegans embryo. The first gene, called let-502, encodes a protein with high similarity to Rho-binding Ser/Thr kinases and to human myotonic dystrophy kinase (DM-kinase). Strong mutations in let-502 block embryonic elongation, and let-502 reporter constructs are expressed in hypodermal cells at the elongation stage of development. The second gene, mel-11, was identified by mutations that act as extragenic suppressors of let-502. mel-11 encodes a protein similar to the 110-to 133-kD regulatory subunits of vertebrate smooth muscle myosin-associated phosphatase (PP-IM). We suggest that the LET-502 kinase and the MEL-11 phosphatase subunit act in a pathway linking a signal generated by the small GTP-binding protein Rho to a myosin-based hypodermal contractile system that drives embryonic elongation. LET-502 may directly regulate the activity of the MEL-11 containing phosphatase complex and the similarity between LET-502 and DM-kinase suggests a similar function for DM-kinase.

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“…Importantly, the expression of MKBP/HSPB2, but not other sHSPs, is specifically up-regulated in the skeletal muscle of myotonic dystrophy patients as if to compensate for the reduced amount of DMPK. Together with the fact that DMPK knock-out mice develop a late-onset, progressive myopathy (25), these findings led us to propose that this kinase is involved in a stressresponse system in muscle cells by being a specific target of MKBP/HSPB2 (23). Furthermore, because MKBP/HSPB2 itself is localized not only at the neuromuscular junction where DMPK is concentrated, but also at the Z-band of myofibrils, we speculated that MKBP/HSPB2 also contributes to the maintenance of myofibril integrity by interacting directly with myofibrils independent of DMPK.…”

mentioning

confidence: 99%

Muscle Develops a Specific Form of Small Heat Shock Protein Complex Composed of MKBP/HSPB2 and HSPB3 during Myogenic Differentiation

Sugiyama

Suzuki

Kishikawa

et al. 2000

Journal of Biological Chemistry

279

255

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Previously, we identified a new mammalian sHSP, MKBP, as a myotonic dystrophy protein kinase-binding protein, and suggested its important role in muscle maintenance (Suzuki, A., Sugiyama, Y., Hayashi, Y., Nyu-i, N., Yoshida, M., Nonaka, I., Ishiura, S., Arahata, K., and Ohno, S. (1998) J. Cell Biol. 140, 1113-1124). In this paper, we develop the former work by performing extensive characterization of five of the six sHSPs so far identified, that is, HSP27, ␣B-crystallin, p20, MKBP/ HSPB2, and HSPB3, omitting lens-specific ␣A-crystallin. Tissue distribution analysis revealed that although each sHSP shows differential constitutive expression in restricted tissues, tissues that express all five sHSPs are only muscle-related tissues. Especially, the expressions of HSPB3, identified for the first time as a 17-kDa protein in this paper, and MKBP/HSPB2 are distinctly specific to muscles. Moreover, these sHSPs form an oligomeric complex with an apparent molecular mass of 150 kDa that is completely independent of the oligomers formed by HSP27, ␣B-crystallin, and p20. The expressions of MKBP/HSPB2 and HSPB3 are induced during muscle differentiation under the control of MyoD, suggesting that the sHSP oligomer comprising MKBP/ HSPB2 and HSPB3 represents an additional system closely related to muscle function. The functional divergence among sHSPs in different oligomers is also demonstrated in several ways: 1) an interaction with myotonic dystrophy protein kinase, which has been suggested to be important for the maintenance of myofibril integrity, was observed only for MKBP/HSPB2; 2) a myotube-specific association with actin bundles was observed for HSP27 and ␣B-crystallin, but not for MKBP/ HSPB2; and 3) sHSPs whose mRNAs are induced by heat shock are ␣B-crystallin and HSP27. Taken together, the results suggest that muscle cells develop two kinds of stress response systems composed of diverged sHSP members, and that these systems work independently in muscle maintenance and differentiation.Heat shock and numerous other stress conditions lead to the rapid induction of several genes whose protein products, collectively called heat shock proteins (HSPs), 1 play protective roles in cell survival (1). Considering that muscles are frequently subjected to severe conditions caused by heat, oxidative, and mechanical stresses, especially during exercise (2), these HSPs may be especially important in this particular tissue. In fact, several HSPs, including HSP60, 70, and 90, have been shown to be induced after exhaustive exercise (3). In addition, the inducible isoform of HSP70 has been shown to be constitutively expressed in a certain type of skeletal muscle fiber (4), suggesting that muscle cells are chronically ready to respond to frequent stresses. However, there have been limited numbers of studies that focus on HSPs in muscle cells.HSPs with low molecular masses of 15-30 kDa are called small heat shock proteins (sHSPs); they commonly share a homologous sequence of about 80 amino acids called the "␣-crystallin domain" (5). Among ...

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Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy

Cited by 321 publications

References 66 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.

Caenorhabditis elegans LET-502 is related to Rho-binding kinases and human myotonic dystrophy kinase and interacts genetically with a homolog of the regulatory subunit of smooth muscle myosin phosphatase to affect cell shape.

Muscle Develops a Specific Form of Small Heat Shock Protein Complex Composed of MKBP/HSPB2 and HSPB3 during Myogenic Differentiation

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