Expansion of germline RPS20 mutation phenotype to include Diamond-Blackfan anemia.,Human Mutation

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Expansion of germline RPS20 mutation phenotype to include Diamond-Blackfan anemia.
Human Mutation ( IF 3.3 ) Pub Date : 2020-08-12 , DOI: 10.1002/humu.24092
Saleh Bhar ₁ , Fujun Zhou ₂ , Lucas C Reineke ₃ , Danna K Morris ₁ , Payal P Khincha ₄ , Neelam Giri ₄ , Lisa Mirabello ₄ , Katie Bergstrom ₁ , Laramie D Lemon ₅ , Christopher L Williams ₁ , Yukimatsu Toh ₁ , M Tarek Elghetany ₆ , Richard E Lloyd ₃ , Blanche P Alter ₄ , Sharon A Savage ₄ , Alison A Bertuch ₁

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Diamond–Blackfan anemia (DBA) is a ribosomopathy of variable expressivity and penetrance characterized by red cell aplasia, congenital anomalies, and predisposition to certain cancers, including early‐onset colorectal cancer (CRC). DBA is primarily caused by a dominant mutation of a ribosomal protein (RP) gene, although approximately 20% of patients remain genetically uncharacterized despite exome sequencing and copy number analysis. Although somatic loss‐of‐function mutations in RP genes have been reported in sporadic cancers, with the exceptions of 5q‐myelodysplastic syndrome (RPS14) and microsatellite unstable CRC (RPL22), these cancers are not enriched in DBA. Conversely, pathogenic variants in RPS20 were previously implicated in familial CRC; however, none of the reported individuals had classical DBA features. We describe two unrelated children with DBA lacking variants in known DBA genes who were found by exome sequencing to have de novo novel missense variants in RPS20. The variants affect the same amino acid but result in different substitutions and reduce the RPS20 protein level. Yeast models with mutation of the cognate residue resulted in defects in growth, ribosome biogenesis, and polysome formation. These findings expand the phenotypic spectrum of RPS20 mutation beyond familial CRC to include DBA, which itself is associated with increased risk of CRC.

中文翻译：

种系 RPS20 突变表型扩展到包括 Diamond-Blackfan 贫血。

Diamond-Blackfan 贫血 (DBA) 是一种表现力和外显率不同的核糖体病，其特征是红细胞发育不全、先天性异常和某些癌症的易感性，包括早发性结直肠癌 (CRC)。DBA 主要是由核糖体蛋白 (RP) 基因的显性突变引起的，尽管尽管进行了外显子组测序和拷贝数分析，但仍有大约 20% 的患者在基因上没有特征。尽管在散发性癌症中已经报道了 RP 基因的体细胞功能丧失突变，但除了 5q 骨髓增生异常综合征 ( RPS14 ) 和微卫星不稳定 CRC ( RPL22 ) 外，这些癌症并未富含 DBA。相反，RPS20 中的致病变异以前与家族性结直肠癌有关；然而，所报告的个人都没有经典的 DBA 特征。我们描述了两个不相关的 DBA 儿童，他们在已知的 DBA 基因中缺乏变异，他们通过外显子组测序发现在RPS20 中具有从头新的错义变异。变体影响相同的氨基酸，但导致不同的取代并降低 RPS20 蛋白水平。具有同源残基突变的酵母模型导致生长、核糖体生物发生和多核糖体形成缺陷。这些发现将RPS20突变的表型谱扩展到家族性 CRC 之外，包括 DBA，DBA 本身与 CRC 风险增加有关。

更新日期：2020-08-12

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