Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.
Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.
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丝氨酸/苏氨酸激酶 NEK8 激酶结构域中的某些杂合变异可导致常染色体显性遗传形式的多囊肾病。
DOI：
10.1016/j.kint.2023.07.021
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发表时间：
2023
影响因子：
19.6
通讯作者：
M
中科院分区：
文献类型：
--
作者：
Claus,LauraR;Chen,Chuan;Stallworth,Jennifer;Turner,JoshuaL;Slaats,GiselaG;Hawks,AlexandraL;Mabillard,Holly;Senum,SarahR;Srikanth,Sujata;Flanagan-Steet,Heather;Louie,RaymondJ;Silver,Josh;Lerner-Ellis,Jordan;Morel,Chantal;M
常染色体显性多囊肾病（ADPKD）是由PKD 1和PKD 2的致病性变异引起的，是PKD最常见的形式，但已确定与原发纤毛功能相关的其他遗传原因。丝氨酸/苏氨酸激酶NEK 8中的双等位基因致病变异体引起伴有肾外表现的综合征性纤毛病变。我们在12个ADPKD家系中发现了NEK 8基因。利用Nek 8基因敲除小鼠肾上皮细胞（IMCD 3）转染野生型或突变型NEK 8，进一步研究纤毛发生、纤毛运输、激酶功能和DNA损伤反应。21个受影响的单等位基因个体一致表现出囊性肾病（大多数是新生儿），没有一致的肾外表现。NEK 8错义突变p.Arg45Trp的复发性新突变，包括嵌合现象，见于10个家族。还鉴定了激酶结构域内其他地方的错义变体（p.Ile150Met和p.Lys157Gln）。功能研究表明NEK 8蛋白正常定位于近端纤毛，并且在患者来源的细胞中没有一致的纤毛形成缺陷。NEK 8-野生型蛋白和Nek 8敲除IMCD 3细胞中表达的蛋白的所有变体形式定位于纤毛并支持纤毛发生。然而，表达NEK 8-p.Arg45Trp和NEK 8-p.Lys157Gln的Nek 8敲除IMCD 3细胞显示出显著降低的多囊蛋白-2但正常的ANKS 6在纤毛中的定位。此外，p.Arg45Trp NEK 8在体外表现出降低的激酶活性。在表达NEK 8-p.Arg45Trp的患者源性类小管和顶CD 3细胞中，与健康的ESTA匹配的对照相比，DNA损伤信号传导增加。因此，我们提出了一个显性负效应的特定杂合错义变异的NEK 8激酶域作为一个新的原因PKD。
Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 andPKD2is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinaseNEK8cause a syndromic ciliopathy with extra-kidney manifestations. Here we identifyNEK8as a disease gene for ADPKD in 12 families. Clinical evaluation was combined with functional studies using fibroblasts and tubuloids from affected individuals.Nek8knockout mouse kidney epithelial (IMCD3) cells transfected with wild type or variantNEK8were further used to study ciliogenesis, ciliary trafficking, kinase function, and DNA damage responses. Twenty-one affected monoallelic individuals uniformly exhibited cystic kidney disease (mostly neonatal) without consistent extra-kidney manifestations. Recurrentde novomutations of theNEK8missense variant p.Arg45Trp, including mosaicism, were seen in ten families. Missense variants elsewhere within the kinase domain (p.Ile150Met and p.Lys157Gln) were also identified. Functional studies demonstrated normal localization of the NEK8 protein to the proximal cilium and no consistent cilia formation defects in patient-derived cells. NEK8-wild type protein and all variant forms of the protein expressed inNek8knockout IMCD3 cells were localized to cilia and supported ciliogenesis. However,Nek8knockout IMCD3 cells expressing NEK8-p.Arg45Trp and NEK8-p.Lys157Gln showed significantly decreased polycystin-2 but normal ANKS6 localization in cilia. Moreover, p.Arg45Trp NEK8 exhibited reduced kinase activityin vitro. In patient derived tubuloids and IMCD3 cells expressing NEK8-p.Arg45Trp, DNA damage signaling was increased compared to healthy passage-matched controls. Thus, we propose a dominant-negative effect for specific heterozygous missense variants in the NEK8 kinase domain as a new cause of PKD.
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影响因子：
64.5
作者：
Chaki M;Airik R;Ghosh AK;Giles RH;Chen R;Slaats GG;Wang H;Hurd TW;Zhou W;Cluckey A;Gee HY;Ramaswami G;Hong CJ;Hamilton BA;Cervenka I;Ganji RS;Bryja V;Arts HH;van Reeuwijk J;Oud MM;Letteboer SJ;Roepman R;Husson H;Ibraghimov-Beskrovnaya O;Yasunaga T;Walz G;Eley L;Sayer JA;Schermer B;Liebau MC;Benzing T;Le Corre S;Drummond I;Janssen S;Allen SJ;Natarajan S;O'Toole JF;Attanasio M;Saunier S;Antignac C;Koenekoop RK;Ren H;Lopez I;Nayir A;Stoetzel C;Dollfus H;Massoudi R;Gleeson JG;Andreoli SP;Doherty DG;Lindstrad A;Golzio C;Katsanis N;Pape L;Abboud EB;Al-Rajhi AA;Lewis RA;Omran H;Lee EY;Wang S;Sekiguchi JM;Saunders R;Johnson CA;Garner E;Vanselow K;Andersen JS;Shlomai J;Nurnberg G;Nurnberg P;Levy S;Smogorzewska A;Otto EA;Hildebrandt F
通讯作者：
Hildebrandt F
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
13.6
作者：
Sohara, Eisei;Luo, Ying;Zhou, Jing
通讯作者：
Zhou, Jing
影响因子：
14.8
作者：
Kinoshita, Eiji;Kinoshita-Kikuta, Emiko;Koike, Tohru
通讯作者：
Koike, Tohru
影响因子：
16
作者：
Choi, Hyo Jei Claudia;Lin, Jia-Ren;Vannier, Jean-Baptiste;Slaats, Gisela G.;Kile, Andrew C.;Paulsen, Renee D.;Manning, Danielle K.;Beier, David R.;Giles, Rachel H.;Boulton, Simon J.;Cimprich, Karlene A.
通讯作者：
Cimprich, Karlene A.