一种新的TAF1C错义变异通过破坏核仁定位和核质聚集导致神经发育退化。

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
S Rehan Ahmad, Natchimuthu Vijayakumar, Nazim Nasir
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引用次数: 0

摘要

TAF1C (TATA盒结合蛋白相关因子,RNA聚合酶I亚基C)是RNA聚合酶I转录机制的重要组成部分,负责核糖体RNA合成和核核功能。最近,TAF1C的变异被认为是早期神经系统综合征的罕见遗传原因,其特征是核核应激和核糖体生物发生受损,导致发育迟缓和脑萎缩。在这里,我们报告了一个新的纯合错义变异(c.1766C >t;p.Ser589Leu)在3岁8个月大的男孩TAF1C中表现出正常的发育,直到2岁,随后出现全身性癫痫发作和进行性神经发育倒退、痉挛、小头畸形和小脑萎缩。MRI显示不对称扩散受限和弥漫性小脑萎缩。尽管突变体TAF1C转录本和蛋白在外周血中表达水平正常,但免疫荧光分析显示核仁定位缺失,核质内形成异常线状聚集体。这些发现表明p.Ser589Leu变异通过功能定位错误而不是表达丧失导致疾病。我们的病例扩展了taf1c相关疾病的表型和机制谱,并强调了适当的亚核定位对维持神经元功能和发育的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Novel TAF1C Missense Variant Causes Neurodevelopmental Regression via Disrupted Nucleolar Localization and Nucleoplasmic Aggregation.

TAF1C (TATA box-binding protein-associated factor, RNA polymerase I subunit C) is an essential component of the RNA polymerase I transcription machinery responsible for ribosomal RNA synthesis and nucleolar function. Variants in TAF1C have recently emerged as rare genetic causes of early-onset neurological syndromes characterized by nucleolar stress and impaired ribosome biogenesis, leading to developmental delay and brain atrophy. Here, we report a novel homozygous missense variant (c.1766C>T; p.Ser589Leu) in TAF1C in a 3-year 8-month-old boy who exhibited normal development until age two, followed by generalized seizures and progressive neurodevelopmental regression, spasticity, microcephaly, and cerebellar atrophy. MRI revealed asymmetric diffusion restriction and diffuse cerebellar atrophy. Although the mutant TAF1C transcript and protein were expressed at normal levels in peripheral blood cells, immunofluorescence analysis revealed a loss of nucleolar localization and the formation of abnormal thread-like aggregates within the nucleoplasm. These findings suggest that the p.Ser589Leu variant causes disease through functional mislocalization rather than loss of expression. Our case expands the phenotypic and mechanistic spectrum of TAF1C-related disorders and highlights the importance of proper subnuclear localization for maintaining neuronal function and development.

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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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