Expansion of germline RPS20 mutation phenotype to include Diamond-Blackfan anemia.
Expansion of germline RPS20 mutation phenotype to include Diamond-Blackfan anemia.
复制标题
种系RPS20突变表型的膨胀，包括钻石 - 黑色贫血。
DOI：
10.1002/humu.24092
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发表时间：
2020-11
期刊：
影响因子：
3.9
通讯作者：
Bertuch AA
中科院分区：
文献类型：
--
作者：
Bhar S;Zhou F;Reineke LC;Morris DK;Khincha PP;Giri N;Mirabello L;Bergstrom K;Lemon LD;Williams CL;Toh Y;Elghetany MT;Lloyd RE;Alter BP;Savage SA;Bertuch AA
Diamond Blackfan贫血（DBA）是一种具有可变表达和外显率的核糖体病，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主要由核糖体蛋白（RP）基因的显性突变引起，尽管尽管外显子组测序和拷贝数分析，大约20%的患者仍然没有遗传特征。虽然在散发性癌症中，除了5q-骨髓增生异常综合征（RPS14）和微卫星不稳定CRC （RPL22）外，已经报道了RP基因的体细胞功能丧失突变，但这些癌症并不富含DBA。相反，RPS20的致病变异先前与家族性结直肠癌有关；然而，报告的个体中没有一个具有典型的DBA特征。我们描述了两个不相关的儿童，他们在已知的DBA基因中缺乏DBA变体，通过外显子组测序发现他们在RPS20中具有全新的错义变体。这些变异影响相同的氨基酸，但导致不同的取代，并降低RPS20蛋白水平。同源残基突变的酵母模型在生长、核糖体生物发生和多体形成方面存在缺陷。这些发现将RPS20突变的表型谱从家族性CRC扩展到包括DBA，而DBA本身与CRC风险增加有关。
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. While 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 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.
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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：
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：
--
作者：
Fancello L;Kampen KR;Hofman IJ;Verbeeck J;De Keersmaecker K
通讯作者：
De Keersmaecker K
影响因子：
20.3
作者：
Choesmel, Valerie;Bacqueville, Daniel;Gleizes, Pierre-Emmanuel
通讯作者：
Gleizes, Pierre-Emmanuel
影响因子：
20.3
作者：
Flygare, Johan;Aspesi, Anna;Ellis, Steven R.
通讯作者：
Ellis, Steven R.