共济失调毛细血管扩张
错义突变
桑格测序
遗传学
生物
生物信息学
疾病
基因
致病性
突变
遗传分析
生物信息学
计算生物学
医学
DNA
病理
DNA损伤
微生物学
作者
Rim Jenni,Hédia Klaa,Oussema Khamessi,Asma Chikhaoui,Dorra Najjar,Kaïs Ghedira,Ichraf Kraoua,Ilhem Turki,Houda Yacoub‐Youssef
标识
DOI:10.1016/j.ijbiomac.2024.134444
摘要
Ataxia Telangiectasia (AT) is a rare multisystemic neurodegenerative disease caused by biallelic mutations in the ATM gene. Few clinical studies on AT disease have been conducted in Tunisia, however, the mutational landscape is still undefined. Our aim is to determine the clinical and genetic spectrum of AT Tunisian patients and to explore the potential underlying mechanism of variant pathogenicity. Sanger sequencing was performed for nine AT patients. A comprehensive computational analysis was conducted to evaluate the possible pathogenic effect of ATM identified variants. Genetic screening of ATM gene has identified nine different variants from which six have not been previously reported. In silico analysis have predicted a pathogenic effect of identified mutations. This was corroborated by a structural bioinformatics study based on molecular modeling and docking for novel missense mutations. Our findings suggest a profound impact of identified mutations not only on the ATM protein stability, but also on the ATM-ligand interactions. Our study characterizes the mutational landscape of AT Tunisian patients which will allow to set up genetic counseling and prenatal diagnosis for families at risk and expand the spectrum of ATM variants worldwide. Furthermore, understanding the mechanism that underpin variant pathogenicity could provide further insights into disease pathogenesis.
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