Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member

Brook, David; McCurrach, Mila E.; Harley, H G; Buckler, Alan; Church, Deanna M.; Aburatani, Hiroyuki; Hunter, Kent W.; Stanton, Vincent P.; Thirion, Jean Paul; Hudson, Thomas J.; Sohn, Robert L.; Zemelman, Boris V.; Snell, Russell G.; Rundle, S.A.; Crow, S; Davies, June; Shelbourne, Peggy; Buxton, Jessica L.; Jones, Christine; Juvonen, Vesa; Johnson, Keith; Harper, Peter S.; Shaw, Duncan; Housman, David E.

doi:10.1016/0092-8674(92)90154-5

Cited by 2,417 publications

(1,469 citation statements)

References 38 publications

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“…MD-PK, which contains a kinase domain and a coiled-coil forming region homologous to ROCK [9,10], is specifically localized to the myotendenous junction of skeletal muscle, the dense plaques of smooth muscle and the intercalated disc of cardiac muscle [19], in which muscle fibers fuse to the membranes and many focal adhesion proteins accumulate. ROCK may also be present in related intracellular compartments and be involved in Rho-mediated cytoskeletal regulation.…”

Section: O Nakagawa Et Al/febs Letters 392 (1996) 189-193mentioning

confidence: 99%

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ROCK‐I and ROCK‐II, two isoforms of Rho‐associated coiled‐coil forming protein serine/threonine kinase in mice

et al. 1996

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We recently identified a novel human protein kinase, p160 ROCK, as a putative downstream target of the small GTPase Rho. Using the human ROCK cDNA as a probe, we isolated cDNA of two distinct, highly related sequences from mouse libraries. One encoded a mouse counterpart of human ROCK (ROCK-I), and the other encoded a novel ROCK-related kinase (ROCK-II). Like ROCK/ROCK-I, ROCK-II also bound to GTP-Rho selectively. ROCK-I mRNA was ubiquitously expressed except in the brain and muscle, whereas ROCK-II mRNA was expressed abundantly in the brain, muscle, heart, lung and placenta. These results suggest that at least two ROCK isoforms are present in a single species and play distinct roles in Rho-mediated signalling pathways.

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Section: O Nakagawa Et Al/febs Letters 392 (1996) 189-193mentioning

confidence: 99%

“…The kinase domain of ROCK shows a significant sequence homology to myotonic dystrophy protein kinase (MD-PK) [9,10]. In this study, we screened mouse cDNA libraries using human pl60 ROCK cDNA as a probe, and identified two related protein kinases.…”

Section: Introductionmentioning

confidence: 99%

ROCK‐I and ROCK‐II, two isoforms of Rho‐associated coiled‐coil forming protein serine/threonine kinase in mice

et al. 1996

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“…The gene is located on chromosome 19q13. 3 and was cloned in 1992 [1,2]. Expansion of an unstable CTG trinucleotide repeat is frequently observed after parent-to-child transmission in DM1 patients.…”

Section: Introductionmentioning

confidence: 99%

The reproductive outcome of female patients with myotonic dystrophy type 1 (DM1) undergoing PGD is not affected by the size of the expanded CTG repeat tract

Verpoest

Seneca

Rademaeker

et al. 2010

J Assist Reprod Genet

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Purpose This study aims to analyze the relationship between trinucleotide repeat length and reproductive outcome in a large cohort of DM1 patients undergoing ICSI and PGD. Methods Prospective cohort study. The effect of trinucleotide repeat length on reproductive outcome per patient was analyzed using bivariate analysis (T-test) and multivariate analysis using Kaplan-Meier and Cox regression analysis. Results Between 1995 and 2005, 205 cycles of ICSI and PGD were carried out for DM1 in 78 couples. The number of trinucleotide repeats does not have an influence on reproductive outcome when adjusted for age, BMI, basal FSH values, parity, infertility status and male or female affected. Cox regression analysis indicates that cumulative live birth rate is not influenced by the number of trinucleotide repeats. The only factor with a significant effect is age (p<0.05). Conclusion There is no evidence of an effect of trinucleotide repeat length on reproductive outcome in patients undergoing ICSI and PGD.

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“…602668) is caused by a (CCTG) n expansion in intron 1 of the CNBP (CCHC-type zinc-finger nucleic acid-binding protein gene, formerly ZNF9, MIM *116955) on chromosome 3q21. [4][5][6][7][8] For DM1, disease severity and age of onset show a strong correlation with the size of the repeat expansion, which is associated with the phenomenon of anticipation. 9 Variation in repeat size and in somatic repeat expansion in different tissues can partly explain the variability of the phenotype.…”

Section: Introductionmentioning

confidence: 99%

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

et al. 2016

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The myotonic dystrophies (DMs) are the most common inherited muscular disorders in adults. In most of the cases, the disease is caused by (CTG) n /(CCTG) n repeat expansions (EXPs) in non-coding regions of the genes DMPK (dystrophia myotonica-protein kinase) and CNBP (CCHC-type zinc-finger nucleic acid-binding protein). The EXP is transcribed into mutant RNAs, which provoke a common pathomechanism that is characterized by misexpression and mis-splicing. In this study, we screened 138 patients with typical clinical features of DM being negative for EXP in the known genes. We sequenced DMPK and CNBPassociated with DM, as well as CELF1 (CUGBP, Elav-like family member 1) and MBNL1 (muscleblind-like splicing regulator 1) -associated with the pathomechanism of DM, for pathogenic variants, addressing the question whether defects in other genes could cause a DM-like phenotype. We identified variants in three unrelated patients in the MBNL1 gene, two of them were heterozygous missense mutations and one an in-frame deletion of three amino acids. The variants were located in different conserved regions of the protein. The missense mutations were classified as potentially pathogenic by prediction tools. Analysis of MBNL1 splice target genes was carried out for one of the patients using RNA from peripheral blood leukocytes (PBL). Analysis of six genes known to show mis-splicing in the skeletal muscle gave no informative results on the effect of this variant when tested in PBL. The association of these variants with the DM phenotype therefore remains unconfirmed, but we hope that in view of the key role of MBNL1 in DM pathogenesis our observations may foster further studies in this direction.

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Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member

Cited by 2,417 publications

References 38 publications

ROCK‐I and ROCK‐II, two isoforms of Rho‐associated coiled‐coil forming protein serine/threonine kinase in mice

ROCK‐I and ROCK‐II, two isoforms of Rho‐associated coiled‐coil forming protein serine/threonine kinase in mice

The reproductive outcome of female patients with myotonic dystrophy type 1 (DM1) undergoing PGD is not affected by the size of the expanded CTG repeat tract

Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype

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