Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR, and several cofactors including the H/ACA box ribonucleoproteins (RNP) Dyskerin, NOP10, GAR1, NAF1, and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure (BMF), and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal-Hreidarsson syndrome (HH), the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Lastly, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.

中文翻译：

---

NHP2缺乏会损害rRNA的生物发生，并导致肺纤维化和Høyeraal-Hreidarsson综合征。

端粒是染色体末端的核蛋白结构。端粒酶复合物由催化亚基TERT，RNA基质hTR和包括H / ACA盒核糖核蛋白（RNP）Dyskerin，NOP10，GAR1，NAF1和NHP2在内的几种辅因子组成，可调节端粒长度。在人类中，端粒长度维持的遗传缺陷可导致广泛的临床过早衰老表现，包括肺纤维化（PF），先天性角化不全（DC），骨髓衰竭（BMF）和易患癌症。迄今为止，仅在两名DC患者中报告了NHP2突变。在这里，我们报告了首例霍亚拉尔-Hreidarsson综合征（HH），DC的严重形式，由NHP2中的双等位基因错义突变引起。此外，我们鉴定了三名携带NHP2杂合突变的PF无关患者。令人惊讶的是，这些患者中的一位在TERT启动子中获得了体细胞突变，这可能赋予了部分血细胞选择性优势。最后，我们证明了人类NHP2的功能缺陷会影响核糖体RNA的生物发生。总之，我们的结果拓宽了NHP2缺乏症的功能性后果和临床范围。