A novel missense variant in RBM10 can cause a mild form of TARP syndrome with developmental delay and dysmorphic features.,Clinical Genetics

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A novel missense variant in RBM10 can cause a mild form of TARP syndrome with developmental delay and dysmorphic features.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-08-19 , DOI: 10.1111/cge.13835
Eri Imagawa ₁ , Tsuyoshi Konuma ₂ , Emalyn E Cork ₁ , George A Diaz _{1,

3} , Kimihiko Oishi _{1,

3}

Affiliation

RBM10, is an RNA binding protein that is important for development by regulating the expression of multiple genes. RBM10 is on the X chromosome, and nonsense and frameshift RBM10 variants cause TARP syndrome in males. In a 4‐year‐old male, we identified a novel maternally inherited missense RBM10 variant in the RRM2 RNA binding domain, c.965C>T, p.Pro322Leu. His clinical features included intellectual disability, developmental delay, growth restriction, hypotonia, and craniofacial malformations. These features were much milder than those described in previously reported cases of TARP syndrome. By in vitro assays, we found that the mutant p.Pro322Leu RBM10 protein retained its specific RNA binding capacity, while gaining a low‐affinity nonspecific RNA binding. It was normally localized to the nucleus, but its expression level was significantly reduced with a significantly short half‐life. These results indicated that the p.Pro322Leu missense variant causes a developmental disorder in humans through a unique loss‐of‐function mechanism.

中文翻译：

RBM10 中的一种新型错义变体可导致具有发育迟缓和畸形特征的轻度 TARP 综合征。

RBM10 是一种 RNA 结合蛋白，通过调节多个基因的表达对发育很重要。RBM10在 X 染色体上，无意义和移码RBM10变体会导致男性出现 TARP 综合征。在一名 4 岁男性中，我们在 RRM2 RNA 结合域中发现了一种新的母系遗传错义RBM10变体，c.965C>T，p.Pro322Leu。他的临床特征包括智力障碍、发育迟缓、生长受限、张力减退和颅面畸形。这些特征比先前报道的 TARP 综合征病例中描述的要温和得多。通过体外通过分析，我们发现突变的 p.Pro322Leu RBM10 蛋白保留了其特异性 RNA 结合能力，同时获得了低亲和力的非特异性 RNA 结合能力。它通常定位于细胞核，但其表达水平显着降低，半衰期显着缩短。这些结果表明，p.Pro322Leu 错义变异通过独特的功能丧失机制导致人类发育障碍。

更新日期：2020-08-19

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