母亲遗传性糖尿病和耳聋(MIDD)是一种复杂的疾病,以多器官临床表现为特征,包括糖尿病,听力损失,和眼科并发症。这项初步研究旨在阐明核遗传学和线粒体遗传学之间复杂的相互作用,表观遗传修饰,以及它们在MIDD发病机制中的潜在意义。
■采用全面的基因组方法来分析受临床特征MIDD影响的西西里家族,对唯一已知的致病m.3243A>G变体为阴性,整合细胞核和线粒体分析的全外显子组测序和全基因组亚硫酸氢盐测序。
■在涉及视网膜稳态的多个核基因中发现了罕见和有害的变异,线粒体功能,和表观遗传调控,而互补的线粒体DNA分析揭示了跨编码电子传递链和ATP合成机制成分的基因的遗传多样性的丰富挂毯。表观遗传分析揭示了整个基因组和线粒体基因组内的显著差异甲基化区域,表明表观遗传调节的细微差别。
■遗传和表观遗传数据的整合突出了核和线粒体调节之间的潜在串扰,与特定的mtDNA变体影响甲基化模式,并可能影响线粒体基因的表达和调节。这项初步研究为MIDD背后的复杂分子机制提供了有价值的见解,强调细胞核和线粒体之间的相互作用,为未来的研究寻找有针对性的治疗干预措施和个性化的疾病管理方法。
UNASSIGNED: Maternally inherited diabetes and deafness (MIDD) is a complex disorder characterized by multiorgan clinical manifestations, including diabetes, hearing loss, and ophthalmic complications. This pilot study aimed to elucidate the intricate interplay between nuclear and mitochondrial genetics, epigenetic modifications, and their potential implications in the pathogenesis of MIDD.
UNASSIGNED: A comprehensive genomic approach was employed to analyze a Sicilian family affected by clinically characterized MIDD, negative to the only known causative m.3243 A > G variant, integrating whole-exome sequencing and whole-genome bisulfite sequencing of both nuclear and mitochondrial analyses.
UNASSIGNED: Rare and deleterious variants were identified across multiple nuclear genes involved in retinal homeostasis, mitochondrial function, and epigenetic regulation, while complementary mitochondrial DNA analysis revealed a rich tapestry of genetic diversity across genes encoding components of the electron transport chain and ATP synthesis machinery. Epigenetic analyses uncovered significant differentially methylated regions across the genome and within the mitochondrial genome, suggesting a nuanced landscape of epigenetic modulation.
UNASSIGNED: The integration of genetic and epigenetic data highlighted the potential crosstalk between nuclear and mitochondrial regulation, with specific
mtDNA variants influencing methylation patterns and potentially impacting the expression and regulation of mitochondrial genes. This pilot study provides valuable insights into the complex molecular mechanisms underlying MIDD, emphasizing the interplay between nucleus and mitochondrion, tracing the way for future research into targeted therapeutic interventions and personalized approaches for disease management.