RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin–NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin–NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.

RNA修饰在细胞功能中起基本作用。H / ACA小核糖核蛋白（snoRNP）复合物可催化伪尿苷酸化作用，该复合物共享四个核心蛋白：dyskerin（DKC1），NOP10，NHP2和GAR1。在突变DKC1，NOP10，或NHP 2引起先天性角化不良（DC），病症，其特征在于端粒耗损。在这里，我们报告了一种表型，包括两个谱系中的肾病综合征，白内障，感觉神经性耳聋，小肠结肠炎和早期致死率：DKC1 p.Glu206Lys的男性和两个纯合NOP10 p.Thr16Met的儿童。杂合DKC1的雌性p.Glu206Lys发生白内障和感觉神经性耳聋，但只有1例X轴失活偏斜，出现肾病综合征。我们在两个家系中都发现了端粒磨损，但是没有皮肤粘膜异常提示DC。两种突变均落在dyskerin-NOP10结合界面的一个区域，与DC无关，从而削弱了dyskerin-NOP10的相互作用，破坏了催化假尿苷化位点。因此，我们发现患者的核糖体RNA（rRNA）中伪尿苷水平降低。斑马鱼DKK1突变体概括了人类的表型，并且在没有端粒磨损的情况下显示出降低的18S伪尿苷化，核糖体失调和细胞周期缺陷。因此，我们认为这种人类疾病是snoRNP假尿苷化缺陷和核糖体功能障碍的结果。