De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability.
De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability.
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DOI：
10.1136/jmedgenet-2021-107751
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发表时间：
2022-10
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
超过1000个基因中的高影响致病性变体涉及孟德尔形式的神经发育障碍（NDD）。本研究描述了28例携带杂合AGO 1编码变异的NDD先证者的分子和临床特征，这些先证者在所有传播已被证实的患者中从头发生（26/28）。总共鉴定出15种导致氨基酸变化或缺失的独特变体：12种错义变体、一个密码子的两个框内缺失和一个导致两个氨基酸残基缺失的典型剪接变体。反复鉴定的变异存在于几个无关的个体中：p。（Phe180del），p.（Leu190Pro），p.（Leu190Arg），p.（Gly199Ser），p.（Val 254 Ile）和p.（Glu376del）。AGO 1编码Argonaute 1蛋白，其在由小的非编码RNA介导的基因沉默途径中发挥作用。三维蛋白质结构预测表明，这些变体可能会改变AGO 1连接域的灵活性，这可能会损害其在mRNA加工中的功能。受影响的个体存在不同严重程度的智力残疾，以及言语和运动延迟，自闭症行为和其他行为表现。我们的研究表明，AGO 1的从头编码变体参与了一种新的单基因形式的NDD，与最近报道的AGO 2相关的NDD高度相似。
High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD). This study describes the molecular and clinical characterization of 28 probands with NDD harboring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28). A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linkers domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behavior and additional behavioral manifestations. Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.
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影响因子：
16.6
作者：
Lessel D;Zeitler DM;Reijnders MRF;Kazantsev A;Hassani Nia F;Bartholomäus A;Martens V;Bruckmann A;Graus V;McConkie-Rosell A;McDonald M;Lozic B;Tan ES;Gerkes E;Johannsen J;Denecke J;Telegrafi A;Zonneveld-Huijssoon E;Lemmink HH;Cham BWM;Kovacevic T;Ramsdell L;Foss K;Le Duc D;Mitter D;Syrbe S;Merkenschlager A;Sinnema M;Panis B;Lazier J;Osmond M;Hartley T;Mortreux J;Busa T;Missirian C;Prasun P;Lüttgen S;Mannucci I;Lessel I;Schob C;Kindler S;Pappas J;Rabin R;Willemsen M;Gardeitchik T;Löhner K;Rump P;Dias KR;Evans CA;Andrews PI;Roscioli T;Brunner HG;Chijiwa C;Lewis MES;Jamra RA;Dyment DA;Boycott KM;Stegmann APA;Kubisch C;Tan EC;Mirzaa GM;McWalter K;Kleefstra T;Pfundt R;Ignatova Z;Meister G;Kreienkamp HJ
通讯作者：
Kreienkamp HJ
影响因子：
16.6
作者：
Miyoshi T;Ito K;Murakami R;Uchiumi T
通讯作者：
Uchiumi T
DOI：
10.1093/bioinformatics/btu137
发表时间：
2014-07-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Kocher JP;Quest DJ;Duffy P;Meiners MA;Moore RM;Rider D;Hossain A;Hart SN;Dinu V
通讯作者：
Dinu V
影响因子：
4.6
作者：
Karamzadeh R;Karimi-Jafari MH;Sharifi-Zarchi A;Chitsaz H;Salekdeh GH;Moosavi-Movahedi AA
通讯作者：
Moosavi-Movahedi AA
影响因子：
14.9
作者：
Pieper U;Webb BM;Dong GQ;Schneidman-Duhovny D;Fan H;Kim SJ;Khuri N;Spill YG;Weinkam P;Hammel M;Tainer JA;Nilges M;Sali A
通讯作者：
Sali A