De novo variants in GATAD2A in individuals with a neurodevelopmental disorder: GATAD2A-related neurodevelopmental disorder.
De novo variants in GATAD2A in individuals with a neurodevelopmental disorder: GATAD2A-related neurodevelopmental disorder.
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DOI：
10.1016/j.xhgg.2023.100198
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发表时间：
2023-07-13
期刊：
影响因子：
--
通讯作者：
Martin, Donna M.
中科院分区：
文献类型：
--
作者：
Werren, Elizabeth A.;Guxholli, Alba;Jones, Natasha;Wagner, Matias;Hannibal, Iris;Granadillo, Jorge L.;Tyndall, Amanda, V;Moccia, Amanda;Kuehl, Ryan;Levandoski, Kristin M.;Day-Salvatore, Debra L.;Wheeler, Marsha;Chong, Jessica X.;Bamshad, Michael J.;Innes, A. Micheil;Pierson, Tyler Mark;Mackay, Joel P.;Bielas, Stephanie L.;Martin, Donna M.
含加塔锌指结构域2A（GATAD 2A）是核小体重塑和脱乙酰酶（NuRD）复合物的亚基。已知NuRD在神经发育和其他过程中调节基因表达。NuRD复合物通过组蛋白去乙酰化和ATP依赖性染色质重塑活性调节染色质状态。一些神经发育障碍（NDD）先前已与NuRD染色质重塑亚复合物（NuRDopathies）的其他组分的变体有关。我们确定了五个人的特点，NDD拥有从头常染色体显性变异GATAD 2A。受影响个体的核心特征包括整体发育迟缓、结构性脑缺陷和颅面畸形。预计这些GATAD 2A变体会影响蛋白剂量和/或与其他NuRD染色质重塑亚基的相互作用。我们提供的证据表明，GATAD 2A错义变体破坏GATAD 2A与CHD 3，CHD 4和CHD 5的相互作用。我们的研究结果扩展了NuRDopathies的列表，并提供了GATAD 2A变体是以前未表征的发育障碍的遗传基础的证据。核小体重塑和去乙酰化酶（NuRD）复合物的几个成员中的遗传变异与不同的神经发育障碍相关。我们的研究结果表明NuRD成员GATAD 2A与神经发育障碍有关，并证明需要确定其他遗传变异以确定NuRD相关疾病的临床谱。
GATA zinc finger domain containing 2A (GATAD2A) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex. NuRD is known to regulate gene expression during neural development and other processes. The NuRD complex modulates chromatin status through histone deacetylation and ATP-dependent chromatin remodeling activities. Several neurodevelopmental disorders (NDDs) have been previously linked to variants in other components of NuRD’s chromatin remodeling subcomplex (NuRDopathies). We identified five individuals with features of an NDD that possessed de novo autosomal dominant variants in GATAD2A. Core features in affected individuals include global developmental delay, structural brain defects, and craniofacial dysmorphology. These GATAD2A variants are predicted to affect protein dosage and/or interactions with other NuRD chromatin remodeling subunits. We provide evidence that a GATAD2A missense variant disrupts interactions of GATAD2A with CHD3, CHD4, and CHD5. Our findings expand the list of NuRDopathies and provide evidence that GATAD2A variants are the genetic basis of a previously uncharacterized developmental disorder. Genetic variants in several members of the nucleosome remodeling and deacetylase (NuRD) complex are associated with distinct neurodevelopmental disorders. Our findings implicate the NuRD member, GATAD2A, in a neurodevelopmental disorder and demonstrate the need to identify additional genetic variants to define the clinical spectrum of NuRD-related disorders.
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影响因子：
9.3
作者：
Li J;Ma Z;Shi M;Malty RH;Aoki H;Minic Z;Phanse S;Jin K;Wall DP;Zhang Z;Urban AE;Hallmayer J;Babu M;Snyder M
通讯作者：
Snyder M
影响因子：
8.8
作者：
Nitarska J;Smith JG;Sherlock WT;Hillege MM;Nott A;Barshop WD;Vashisht AA;Wohlschlegel JA;Mitter R;Riccio A
通讯作者：
Riccio A
影响因子：
4.8
作者：
Brackertz, M;Boeke, J;Renkawitz, R
通讯作者：
Renkawitz, R
影响因子：
3.7
作者：
Marino S;Nusse R
通讯作者：
Nusse R
影响因子：
8.8
作者：
Spruijt, Cornelia G.;Luijsterburg, Martijn S.;Vermeulen, Michiel
通讯作者：
Vermeulen, Michiel