ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder.
ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder.
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DOI：
10.1016/j.ajhg.2017.11.006
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发表时间：
2017-12-07
影响因子：
9.8
通讯作者：
Banka S
中科院分区：
文献类型：
--
作者：
Cuvertino S;Stuart HM;Chandler KE;Roberts NA;Armstrong R;Bernardini L;Bhaskar S;Callewaert B;Clayton-Smith J;Davalillo CH;Deshpande C;Devriendt K;Digilio MC;Dixit A;Edwards M;Friedman JM;Gonzalez-Meneses A;Joss S;Kerr B;Lampe AK;Langlois S;Lennon R;Loget P;Ma DYT;McGowan R;Des Medt M;O'Sullivan J;Odent S;Parker MJ;Pebrel-Richard C;Petit F;Stark Z;Stockler-Ipsiroglu S;Tinschert S;Vasudevan P;Villa O;White SM;Zahir FR;DDD Study;Woolf AS;Banka S
ACTB编码β-肌动蛋白，一种丰富的细胞骨架管家蛋白。在人类中，假定的功能获得性错义突变导致Baraitser-Winter综合征（BRWS），其特征为智力残疾、皮质畸形、缺损、感觉神经性耳聋和典型的面部特征。迄今为止，ACTB功能丧失突变的后果尚未得到最终证实。我们描述了33例患有发育迟缓、明显智力残疾、内脏器官畸形频率增加的个体的杂合ACTB缺失、无义突变和移码突变（包括心脏和肾脏），生长迟缓，以及可识别的面部完形（间断的波浪眉毛，浓密的睫毛，宽鼻子，宽嘴和突出的下巴），这与BRWS个体的特征不同。引人注目的是，这一光谱与几种染色质重塑发育障碍重叠。在野生型小鼠胚胎中，β-肌动蛋白表达在肾脏、心脏和大脑中突出。与对照细胞相比，淋巴母细胞系和受影响个体的成纤维细胞中ACTB mRNA表达水平降低。来源于受影响个体的成纤维细胞和野生型成纤维细胞中ACTB siRNA敲低显示改变的细胞形状和迁移，与细胞质β-肌动蛋白的已知作用一致。我们还证明，ACTB单倍不足导致细胞增殖减少，细胞周期基因的表达改变，以及细胞核而非细胞质β-肌动蛋白的量减少。总之，我们发现杂合子功能丧失型ACTB突变导致一种明显的多效性畸形综合征伴智力残疾。我们的生物学研究表明，这种蛋白质的严重减少会改变细胞的形状，迁移，增殖和基因表达，从而损害大脑，心脏和肾脏的发育。
ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.
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DOI：
10.1056/nejmoa1515792
发表时间：
2016-06-09
期刊：
The New England journal of medicine
影响因子：
--
作者：
Tarailo-Graovac M;Shyr C;Ross CJ;Horvath GA;Salvarinova R;Ye XC;Zhang LH;Bhavsar AP;Lee JJ;Drögemöller BI;Abdelsayed M;Alfadhel M;Armstrong L;Baumgartner MR;Burda P;Connolly MB;Cameron J;Demos M;Dewan T;Dionne J;Evans AM;Friedman JM;Garber I;Lewis S;Ling J;Mandal R;Mattman A;McKinnon M;Michoulas A;Metzger D;Ogunbayo OA;Rakic B;Rozmus J;Ruben P;Sayson B;Santra S;Schultz KR;Selby K;Shekel P;Sirrs S;Skrypnyk C;Superti-Furga A;Turvey SE;Van Allen MI;Wishart D;Wu J;Wu J;Zafeiriou D;Kluijtmans L;Wevers RA;Eydoux P;Lehman AM;Vallance H;Stockler-Ipsiroglu S;Sinclair G;Wasserman WW;van Karnebeek CD
通讯作者：
van Karnebeek CD
影响因子：
9.8
作者：
Kasher, Paul R.;Schertz, Katherine E.;Banka, Siddharth
通讯作者：
Banka, Siddharth
影响因子：
3.5
作者：
Banka, S.;Lederer, D.;Donnai, D.
通讯作者：
Donnai, D.
影响因子：
30.8
作者：
Santen, Gijs W. E.;Aten, Emmelien;Kriek, Marjolein
通讯作者：
Kriek, Marjolein
影响因子：
4.5
作者：
Petrovski S;Wang Q;Heinzen EL;Allen AS;Goldstein DB
通讯作者：
Goldstein DB