A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families.
A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families.
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作者：
线粒体疾病的遗传结构继续扩大，目前超过350个致病基因。RTN4IP1的双等位基因变异，也被称为视神经萎缩-10 (OPA10)，可导致患者早发性隐性视神经病变、萎缩和脑病。已知该基因编码线粒体泛醇氧化还原酶，该酶与网状蛋白4相互作用，被认为是线粒体抗氧化剂NADPH氧化还原酶。在这里，我们描述了来自沙特阿拉伯北部地区的两个不相关的近亲家庭，其中包含该基因的错义变体（RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe）。临床发病个体表现为智力残疾、脑病、共济失调、视神经萎缩和癫痫发作。基于全外显子组测序和验证性Sanger测序，该变异在家族中与表型完全分离，在大的种族匹配对照和许多内部外显子组中不存在，并通过不同的硅分类器预测具有致病性。结构建模和免疫印迹分析强烈表明该变异具有致病性。由于这些家族属于沙特阿拉伯的一个部落居民，我们假设这个变体很可能是一个创始人。我们提供了该变异的估计年龄，并提供了证实该创始变异的疾病因果关系的数据。
The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant.
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影响因子：
14.9
作者：
Howe KL;Achuthan P;Allen J;Allen J;Alvarez-Jarreta J;Amode MR;Armean IM;Azov AG;Bennett R;Bhai J;Billis K;Boddu S;Charkhchi M;Cummins C;Da Rin Fioretto L;Davidson C;Dodiya K;El Houdaigui B;Fatima R;Gall A;Garcia Giron C;Grego T;Guijarro-Clarke C;Haggerty L;Hemrom A;Hourlier T;Izuogu OG;Juettemann T;Kaikala V;Kay M;Lavidas I;Le T;Lemos D;Gonzalez Martinez J;Marugán JC;Maurel T;McMahon AC;Mohanan S;Moore B;Muffato M;Oheh DN;Paraschas D;Parker A;Parton A;Prosovetskaia I;Sakthivel MP;Salam AIA;Schmitt BM;Schuilenburg H;Sheppard D;Steed E;Szpak M;Szuba M;Taylor K;Thormann A;Threadgold G;Walts B;Winterbottom A;Chakiachvili M;Chaubal A;De Silva N;Flint B;Frankish A;Hunt SE;IIsley GR;Langridge N;Loveland JE;Martin FJ;Mudge JM;Morales J;Perry E;Ruffier M;Tate J;Thybert D;Trevanion SJ;Cunningham F;Yates AD;Zerbino DR;Flicek P
通讯作者：
Flicek P
DOI：
10.1093/brain/awaa459
发表时间：
2021-04-12
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Sanderson LE;Lanko K;Alsagob M;Almass R;Al-Ahmadi N;Najafi M;Al-Muhaizea MA;Alzaidan H;AlDhalaan H;Perenthaler E;van der Linde HC;Nikoncuk A;Kühn NA;Antony D;Owaidah TM;Raskin S;Vieira LGDR;Mombach R;Ahangari N;Silveira TRD;Ameziane N;Rolfs A;Alharbi A;Sabbagh RM;AlAhmadi K;Alawam B;Ghebeh H;AlHargan A;Albader AA;Binhumaid FS;Goljan E;Monies D;Mustafa OM;Aldosary M;AlBakheet A;Alyounes B;Almutairi F;Al-Odaib A;Aksoy DB;Basak AN;Palvadeau R;Trabzuni D;Rosenfeld JA;Karimiani EG;Meyer BF;Karakas B;Al-Mohanna F;Arold ST;Colak D;Maroofian R;Houlden H;Bertoli-Avella AM;Schmidts M;Barakat TS;van Ham TJ;Kaya N
通讯作者：
Kaya N
影响因子：
12.7
作者：
AlMuhaizea, Mohammed;AlMass, Rawan;Kaya, Namik
通讯作者：
Kaya, Namik
影响因子：
12.7
作者：
Perenthaler, Elena;Nikoncuk, Anita;Barakat, Tahsin Stefan
通讯作者：
Barakat, Tahsin Stefan
影响因子：
64.8
作者：
Chen, MS;Huber, AB;Schwab, ME
通讯作者：
Schwab, ME