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1.
Neurosci Res ; 157: 58-63, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31348995

RESUMO

Chronic progressive external ophthalmoplegia (CPEO) is one of the most common mitochondrial disorders. It is characterized by bilateral, slowly progressing loss of extraocular muscle mobility, orbicularis oculi weakness, ptosis, and other neuromuscular symptoms, which are caused by the accumulation of multiple mitochondrial DNA (mtDNA) deletions. Many mutations in different nuclear genes, such as POLG1, POLG2, ANT1, and others, have been described as causing autosomal-inherited CPEO with multiple mtDNA deletions. Most causative genes are involved in mtDNA replication impairment. Here, we report a family with CPEO-like symptoms characterized by multiple muscle mtDNA deletions, ptosis, diabetes, hearing loss, mental retardation, and emotional instability. We performed genetic analyses to identify nuclear gene mutations in the family. DNA from the proband was analyzed by whole-exome sequencing. In addition to possible pathogenic mutations, rare variants were prioritized for gene-functional phenotype interpretation. We found possible pathogenetic mutations in the PRIMPOL, BRCA1, CPT2, and GJB2 genes, and functional polymorphisms in the CARD8, and MEFV genes. Multiple functional polymorphisms and possible pathogenic mutations may contribute to mitochondrial-disease-like phenotypes in a composite manner.


Assuntos
DNA Primase , DNA Polimerase Dirigida por DNA , Variação Genética , Enzimas Multifuncionais , Mutação , Oftalmoplegia Externa Progressiva Crônica , Fenótipo , Proteínas Adaptadoras de Sinalização CARD/genética , DNA Primase/genética , DNA Polimerase Dirigida por DNA/genética , Humanos , Mitocôndrias/genética , Enzimas Multifuncionais/genética , Mutação/genética , Proteínas de Neoplasias/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia Externa Progressiva Crônica/patologia , Polimorfismo Genético , Pirina/genética , Sequenciamento do Exoma
2.
Neurol Genet ; 5(3): e332, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192303

RESUMO

OBJECTIVE: To identify mutations in vacuolar protein sorting 13A (VPS13A) for Japanese patients with suspected chorea-acanthocytosis (ChAc). METHODS: We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the VPS13A gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of VPS13A gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases. RESULTS: We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60-61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan. CONCLUSIONS: We identified 13 different mutations in VPS13A, including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.

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