Myotonic Dystrophy Mutation: an Unstable CTG Repeat in the 3′ Untranslated region of the Gene

Mahadevan, Mani S.; Tsilfidis, Catherine; Sabourin, Luc A.; Shutler, Gary; Amemiya, Chris T.; Jansen, Gert; Neville, Catherine; Narang, Monica A.; Barceló, Juana; O'Hoy, K

doi:10.1126/science.1546325

Cited by 1,496 publications

(847 citation statements)

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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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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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“…The severity of CDM confirmed to correspond to the length of CTG repeats in mutant genes from peripheral blood leukocytes in our study. Mahadevan et al (1992) suggested that a blurred or smeared appearance of expanded alleles seen on Southern blots in lymphocytes indicated somatic cell heterogeneity in the size of the expanded alleles. We also observed smeared expanded bands in several DM patients on Southern blots.…”

Section: Discussionmentioning

confidence: 99%

“…PCR was performed using CTG region-flanking primers Mahadevan et al, 1992). Cycling conditions were as follows: initial denaturation at 95°C for 3 min, 35 cycles at 95°C for 1.5 min, 65°C for l min and at 72°C for 2 min, followed by a final stage at 72°C for 7 min.…”

Section: Methodsmentioning

confidence: 99%

“…The full length of mRNA of the DM kinase gene is estimated to be approximately 3.4 kb and encodes a 69-kDa translational product of 629 amino acids which has no homology to any known protein sequences. The molecular basis of DM mutation is an unstable trinucleotide (CTG) repeat, located at the Y end of a transcript encoding a putative serine/threonine protein kinase Buxton et aL, 1992;Mahadevan et al, 1992;Fu et al, 1992). The number of expansions varies markedly, even in a normal population from 5 to 30, but in DM patients it ranges from 50 to several thousand copies .…”

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confidence: 99%

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Detection of the CTG repeat expansion in congenital myotonic dystrophy

et al. 1997

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SummaryMyotonic dystrophy (DM) is caused by an abnormal expansion of an unstable CTG trinucleotide repeat in the 3" untranslated region of mRNA encoding a putative serine/threonine protein kinase. We analyzed 59 patients with DM (28 congenital DM families: 27 families with maternal transmission and 1 paternal transmission) and 27 normal control subjects to evaluate their CTG repeat size between DM patients and the normal controls, and to search for a correlation between the clinical characteristics of congenital DM (CDM) and CTG repeat expansions. Analysis was on the basis of the Southern blot and polymerase chain reaction (PCR) methods, and by direct sequencing of PCR amplified CTG repeats. Analysis of intergenerational differences in the CTG repeat size for mother-child pairs showed a positive correlation (y= 1.0384x+ 1265.2, rz=0.311). In addition to the strong parental bias, this group showed genetic anticipation. There was a significant correlation of the CTG repeat expansion with disease severity. The largest CTG repeat expansion (2,293 CTG repeats) on average belonged to the severe CDM group, and the smallest (129 CTG repeats) to the subclinical DM group. The mutant allele of an asymptomatic father in the paternally transmitted pedigree revealed 75 CTG repeats, demonstrating that he was a DM protomutation carrier.

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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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Myotonic Dystrophy Mutation: an Unstable CTG Repeat in the 3′ Untranslated region of the Gene

Cited by 1,496 publications

References 12 publications

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

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

Detection of the CTG repeat expansion in congenital myotonic dystrophy

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

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