RESUMO
The autosomal recessive demyelinating form of Charcot-Marie-Tooth can be due to SH3TC2 gene pathogenic variants (CMT4C, AR-CMTde-SH3TC2). We report on a series of 13 patients with AR-CMTde-SH3TC2 among a French cohort of 350 patients suffering from all type of inheritance peripheral neuropathy. The SH3TC2 gene appeared to be the most frequently mutated gene for demyelinating neuropathy in this series by NGS. Four new pathogenic variants have been identified: two nonsense variants (p.(Tyr970*), p.(Trp1199*)) and two missense variants (p.(Leu1126Pro), p.(Ala1206Asp)). The recurrent variant p.Arg954* was present in 62%, and seems to be a founder mutation. The phenotype is fairly homogeneous, as all these patients, except the youngest ones, presented scoliosis and/or hearing loss.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Surdez/genética , Variação Genética/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Escoliose/genética , Adulto , Idoso , Doença de Charcot-Marie-Tooth/epidemiologia , Criança , Estudos de Coortes , Surdez/epidemiologia , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Escoliose/epidemiologia , Adulto JovemRESUMO
SUMMARY: In order to help molecular geneticists to rapidly identify CNVs responsible for inherited diseases among amplicons sequencing data generated by NGS, we designed a user-friendly tool ' Cov'Cop '. Using the run's coverage file provided by the sequencer, Cov'Cop simultaneously analyzes all the patients of the run using a two-stage algorithm containing correction and normalization levels and provides an easily understandable output, showing with various colors, potentially deleted and duplicated amplicons. AVAILABILITY AND IMPLEMENTATION: https://git.unilim.fr/merilp02/CovCop. CONTACT: asliabaldini@unilim.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Variações do Número de Cópias de DNA , Análise Mutacional de DNA/métodos , Software , Algoritmos , Doenças Genéticas Inatas/genética , HumanosRESUMO
A (CTG)nexpansion in the 3'-untranslated region (UTR) of the DM protein kinase gene ( DMPK ) is responsible for causing myotonic dystrophy (DM). Major instability, with very large expansions between generations and high levels of somatic mosaicism, is observed in patients. There is a good correlation between repeat size (at least in leucocytes), clinical severity and age of onset. The trinucleotide repeat instability mechanisms involved in DM and other human genetic diseases are unknown. We studied somatic instability by measuring the CTG repeat length at several ages in various tissues of transgenic mice carrying a (CTG)55expansion surrounded by 45 kb of the human DM region, using small-pool PCR. These mice have been shown to reproduce the intergenerational and somatic instability of the 55 CTG repeat suggesting that surrounding sequences and the chromatin environment are involved in instability mechanisms. As observed in some of the tissues of DM patients, there is a tendency for repeat length and somatic mosaicism to increase with the age of the mouse. Furthermore, we observed no correlation between the somatic mutation rate and tissue proliferation capacity. The somatic mutation rates in different tissues were also not correlated to the relative inter-tissue difference in transcriptional levels of the three genes (DMAHP , DMPK and 59) surrounding the repeat.
Assuntos
Distrofia Miotônica/genética , Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Proteínas Serina-Treonina Quinases/genética , Sequências Repetitivas de Ácido Nucleico , Transcrição Gênica , Fatores Etários , Animais , Divisão Celular , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Miotonina Proteína QuinaseRESUMO
Myotonic dystrophy (DM) is associated with the expansion of a (CTG)n trinucleotide repeat in the 3' untranslated region (UTR) of the DM protein kinase gene (DMPK). The (CTG)n repeat is polymorphic and varies in size between 5 and 37 repeats in unaffected individuals whereas in affected patients there are between 50 and 4,000 CTGs. The size of the (CTG)n repeat, which increases through generations, generally correlates with clinical severity and age of onset. The instability of the CTG repeat appears to depend on its size as well as on the sex of the transmitting parent. Moreover, mitotic instability analysis of different human DM tissues shows length mosaicism between different cell lineages. The molecular mechanisms of triplet instability remain elusive. To investigate the role of genomic sequences in instability, we produced transgenic mice containing a 45-kb genomic segment with a 55-CTG repeat cloned from a mildly affected patient. In contrast to other mouse models containing CAG repeats within cDNAs, these mice showed both intergenerational and somatic repeat instability.
Assuntos
Distrofia Miotônica/genética , Transgenes/genética , Repetições de Trinucleotídeos , Animais , Cosmídeos/genética , DNA Complementar/genética , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mosaicismo , Mutação , Reação em Cadeia da PolimeraseRESUMO
Expansion of (C+G)-rich trinucleotide repeats has been shown to be associated with several autosomal or X-linked genetic diseases and/or fragile sites. By analysing the sequences available in the databases, we found, in a significant proportion of triplet associated genes or fragile sites (11/12), a CpG island close to the trinucleotide repeat. This association led us to assume that flanking regions and chromatin structure near the triplets might play a role in repeat instability.