A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome.
A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome.
复制标题
DOI：
10.1038/s41598-021-88911-3
复制
发表时间：
2021-05-05
影响因子：
4.6
通讯作者：
Findlay GM
中科院分区：
文献类型：
--
作者：
Bustos F;Espejo-Serrano C;Segarra-Fas A;Toth R;Eaton AJ;Kernohan KD;Wilson MJ;Riley LG;Findlay GM
Tonne-Kalscheuer综合征（TOKAS）是一种X连锁智力残疾综合征，伴有多种临床特征，包括颅面畸形、生殖器发育不良和疝。TOKAS仅由编码E3泛素连接酶基因RLIM（也称为RNF 12）的基因中的变体引起。在这里，我们报告了一个新的RLIM错义变体，c.1262A>G p的鉴定。（Tyr 421 Cys），其引起严重形式的TOKAS，导致围产期因脑疝致死。遗传和X染色体失活模式牵连RLIM p。（Tyr 421 Cys）作为受影响个体和亲属内的可能致病性变体。我们表明，RLIM P。（Tyr 421 Cys）变体破坏胚胎干细胞模型中蛋白质的表达和功能。RLIM p.（Tyr 421 Cys）正确定位于细胞核，但容易被蛋白酶体降解。RLM P。（Tyr 421 Cys）变体还显示出显著受损的E3泛素连接酶活性，这干扰了RLIM在启动印迹X染色体失活的Xist长非编码RNA诱导中的功能。我们的数据揭示了RLIM中一种高度破坏性的错义变体，该变体导致严重形式的TOKAS，从而扩展了我们对疾病严重程度的分子和表型谱的理解。
Tonne–Kalscheuer syndrome (TOKAS) is an X-linked intellectual disability syndrome associated with variable clinical features including craniofacial abnormalities, hypogenitalism and diaphragmatic hernia. TOKAS is caused exclusively by variants in the gene encoding the E3 ubiquitin ligase gene RLIM, also known as RNF12. Here we report identification of a novel RLIM missense variant, c.1262A>G p.(Tyr421Cys) adjacent to the regulatory basic region, which causes a severe form of TOKAS resulting in perinatal lethality by diaphragmatic hernia. Inheritance and X-chromosome inactivation patterns implicate RLIM p.(Tyr421Cys) as the likely pathogenic variant in the affected individual and within the kindred. We show that the RLIM p.(Tyr421Cys) variant disrupts both expression and function of the protein in an embryonic stem cell model. RLIM p.(Tyr421Cys) is correctly localised to the nucleus, but is readily degraded by the proteasome. The RLIM p.(Tyr421Cys) variant also displays significantly impaired E3 ubiquitin ligase activity, which interferes with RLIM function in Xist long-non-coding RNA induction that initiates imprinted X-chromosome inactivation. Our data uncover a highly disruptive missense variant in RLIM that causes a severe form of TOKAS, thereby expanding our understanding of the molecular and phenotypic spectrum of disease severity.
登录
查看更多内容
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
11.8
作者：
Bustos F;Segarra-Fas A;Nardocci G;Cassidy A;Antico O;Davidson L;Brandenburg L;Macartney TJ;Toth R;Hastie CJ;Moran J;Gourlay R;Varghese J;Soares RF;Montecino M;Findlay GM
通讯作者：
Findlay GM
影响因子：
11
作者：
Hu H;Haas SA;Chelly J;Van Esch H;Raynaud M;de Brouwer AP;Weinert S;Froyen G;Frints SG;Laumonnier F;Zemojtel T;Love MI;Richard H;Emde AK;Bienek M;Jensen C;Hambrock M;Fischer U;Langnick C;Feldkamp M;Wissink-Lindhout W;Lebrun N;Castelnau L;Rucci J;Montjean R;Dorseuil O;Billuart P;Stuhlmann T;Shaw M;Corbett MA;Gardner A;Willis-Owen S;Tan C;Friend KL;Belet S;van Roozendaal KE;Jimenez-Pocquet M;Moizard MP;Ronce N;Sun R;O'Keeffe S;Chenna R;van Bömmel A;Göke J;Hackett A;Field M;Christie L;Boyle J;Haan E;Nelson J;Turner G;Baynam G;Gillessen-Kaesbach G;Müller U;Steinberger D;Budny B;Badura-Stronka M;Latos-Bieleńska A;Ousager LB;Wieacker P;Rodríguez Criado G;Bondeson ML;Annerén G;Dufke A;Cohen M;Van Maldergem L;Vincent-Delorme C;Echenne B;Simon-Bouy B;Kleefstra T;Willemsen M;Fryns JP;Devriendt K;Ullmann R;Vingron M;Wrogemann K;Wienker TF;Tzschach A;van Bokhoven H;Gecz J;Jentsch TJ;Chen W;Ropers HH;Kalscheuer VM
通讯作者：
Kalscheuer VM
影响因子：
5.2
作者：
Tonne, Elin;Holdhus, Rita;Fiskerstrand, Torunn
通讯作者：
Fiskerstrand, Torunn
影响因子：
4.5
作者：
Barakat, Tahsin Stefan;Gunhanlar, Nilhan;Gribnau, Joost
通讯作者：
Gribnau, Joost