Postzygotic instability of the myotonic dystrophy p[AGC]n repeat supported by larger expansions in muscle and reduced amplifications in sperm

Massari, Antonella; Gennarelli, Massimo; Menegazzo, E.; Pizzuti, Antonio; Silani, Vincenzo; Mastrogiacomo, I.; Pagani, E.; Angelini, C.; Scarlato, G.; Novelli, Giuseppe; Dallapiccola, Bruno

doi:10.1007/bf00868393

Cited by 13 publications

(5 citation statements)

References 32 publications

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“…12,17 Although we have detected expansions Ͼ1000 repeats in two men (DM1-S19 and DM1-S31), large expansions still appear to be limited to Ͻ1,500 repeats, and expansions Ͼ1000 are not observed in the majority of men. However, this effect was much more evident for the premutations and protomutations and seemed to tail off significantly for full mutation alleles, which showed high levels of individual specific variation.…”

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confidence: 68%

Germline mutational dynamics in myotonic dystrophy type 1 males

et al. 2004

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confidence: 68%

Germline mutational dynamics in myotonic dystrophy type 1 males

et al. 2004

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“…Our suggestion is also consistent with the direct analysis of CTG lengths in sperm that suggested an increase of germline contraction frequencies for fathers with larger alleles. 63,[93][94][95][96] We previously demonstrated that DM1 mouse tissues with lowest adjacent methylation showed the most asymmetric DM1 replication fork profiles, that may alter repeat instability. 92 In spermatocytes, an absence of methylation would permit binding of the CTCF paralog CTCFL, which may stabilize or induce contractions of large CTG tracts, just as CTCF binding appears to promote repeat stability in somatic tissues.…”

Section: Discussionmentioning

confidence: 99%

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy

Barbé

Lanni

López-Castel

et al. 2017

The American Journal of Human Genetics

128

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CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.

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“…One primer, primer 102, was fluorescently labeled with a 6-FAM dye phosphoramidite. PCR amplification was performed in a final reaction volume of 25 pl containing 200 ng of genomic DNA, 5 pmol of each primer, 10 mM Tris-HC1, pH 8.3,50 mM KCl, 1 mM MgCl,, 200 pM each dNTP and 1.25 U of Tuq polymerase (AmpliTaqTM DNA Polymerase, PE Applied Biosystems, Foster City, CA).…”

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Genotype ‐phenotype correlation in myotonic dystrophy

Gharehbaghi-Schneli¹,

Finsterei²,

Korschineck³

et al. 1998

Clinical Genetics

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Myotonic dystrophy (DM) is caused by a mutation in the length of a trinucleotide (CTG) repeat in the 3' untranslated region of the my‐otonin protein kinase gene located on chromosome 19q13.3. The normal gene has between 5 and 36 CTG trinucleotide repeats, whereas minimally affected individuals have 50 copies and severely affected DM‐patients have several thousands of such repeats. Since no information on a genotype‐phenotype correlation in Austrian DM‐patients is available, we examined a small group of these patients for the unstable trinucleotide repeat. Molecular analysis was used to clarify equivocal clinical diagnoses and confirm clinical findings. We studied eight DM‐families, a total of 57 individuals, of whom 18 were diagnosed with a trinucleotide repeat expansion. Twenty‐six unrelated individuals served as a control. Clinical assessment was based on the muscular disability rating scale (MDRS) and a sum of symptoms score (SSS). There was a significant correlation between the clinical scores (MDRS: Spearman r = 0.51: p = 0.029; SSS: Spearman r = 0.538; p = 0.0259) used and the size of the amplification of the trinucleotide repeat. The largest expansion found in our group of patients was 6 kb. Furthermore, we observed both expansion and contraction of the enlarged fragment during transmission from one generation to the next.

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Postzygotic instability of the myotonic dystrophy p[AGC]n repeat supported by larger expansions in muscle and reduced amplifications in sperm

Cited by 13 publications

References 32 publications

Germline mutational dynamics in myotonic dystrophy type 1 males

Germline mutational dynamics in myotonic dystrophy type 1 males

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy

Genotype ‐phenotype correlation in myotonic dystrophy

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