Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia.
Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia.
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DOI：
10.1002/jbmr.4177
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Mäkitie O
中科院分区：
文献类型：
--
作者：
Costantini A;Alm JJ;Tonelli F;Valta H;Huber C;Tran AN;Daponte V;Kirova N;Kwon YU;Bae JY;Chung WY;Tan S;Sznajer Y;Nishimura G;Näreoja T;Warren AJ;Cormier-Daire V;Kim OH;Forlino A;Cho TJ;Mäkitie O
脊柱干骺端发育不良（SEMD）是一组异质性疾病，具有可变的生长障碍和影响脊柱和长骨骨骺和干骺端的骨骼损伤。在这里，我们报告四个不相关的家庭与SEMD中，我们确定了两个单等位基因错义变异体和一个单等位基因剪接位点变异体RPL 13，编码的核糖体蛋白eL 13。在四个家庭中的两个中，我们观察到常染色体显性遗传，具有不完全遗传和可变的临床表现;突变阳性受试者的表型范围从正常身高伴或不伴髋关节发育不良到重度SEMD伴严重身材矮小和明显骨骼发育不良。对携带RPL 13错义突变的患者来源的真皮成纤维细胞的体外研究表明，eL 13表达正常，具有适当的亚细胞定位，但与eL 28的共定位减少（p < 0.001）。来自突变阳性受试者的成纤维细胞中的细胞功能缺陷表明60 S亚基与80 S核糖体的比率显著增加（p = 0.007）和整体翻译减弱（p = 0.017）。与人类表型一致，我们通过CRISPR-Cas9编辑产生的rpl 13突变斑马鱼模型在胚胎和幼年阶段显示出软骨畸形。这些发现扩展了RPL 13突变的遗传谱，导致这种具有可变骨骼特征的新型人类核糖体病。我们的研究首次强调了SEMD-RPL 13型的不完全突变和广泛的表型变异性，并证实了核糖体功能受损。此外，新产生的rpl 13突变体斑马鱼模型证实了eL 13在骨骼发生中的作用。版权所有2020作者。《骨与矿物质研究杂志》由Wiley Periodicals LLC代表美国骨与矿物质研究学会（ASBMR）出版。
Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation‐positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient‐derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation‐positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR‐Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD‐RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
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影响因子：
3.5
作者：
Cadoff, E. B.;Sheffer, R.;Schwarzbauer, J. E.
通讯作者：
Schwarzbauer, J. E.
影响因子：
3.5
作者：
Gioia R;Tonelli F;Ceppi I;Biggiogera M;Leikin S;Fisher S;Tenedini E;Yorgan TA;Schinke T;Tian K;Schwartz JM;Forte F;Wagener R;Villani S;Rossi A;Forlino A
通讯作者：
Forlino A
影响因子：
3.9
作者：
Boria, Ilenia;Garelli, Emanuela;Gazda, Hanna T.;Aspesi, Anna;Quarello, Paola;Pavesi, Elisa;Ferrante, Daniela;Meerpohl, Joerg J.;Kartal, Mutlu;Da Costa, Lydie;Proust, Alexis;Leblanc, Thierry;Simansour, Maud;Dahl, Niklas;Froejmark, Anne-Sophie;Pospisilova, Dagmar;Cmejla, Radek;Beggs, Alan H.;Sheen, Mee R.;Landowski, Michael;Buros, Christopher M.;Clinton, Catherine M.;Dobson, Lori J.;Vlachos, Adrianna;Atsidaftos, Eva;Lipton, Jeffrey M.;Ellis, Steven R.;Ramenghi, Ugo;Dianzani, Irma
通讯作者：
Dianzani, Irma
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
5.2
作者：
Costantini A;Skarp S;Kämpe A;Mäkitie RE;Pettersson M;Männikkö M;Jiao H;Taylan F;Lindstrand A;Mäkitie O
通讯作者：
Mäkitie O