INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée La Ligue contre le Cancer, Paris, France.
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Hum Mol Genet. 2020 Apr 15;29(6):907-922. doi: 10.1093/hmg/ddaa011.
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 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 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, 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. Finally, 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.
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 和几个辅助因子组成，包括 H/ACA 盒核蛋白 Dyskerin、NOP10、GAR1、NAF1 和 NHP2，调节端粒长度。在人类中，端粒长度维持的遗传缺陷负责广泛的临床早老症表现，包括肺纤维化 (PF)、先天性角化不良 (DC)、骨髓衰竭和癌症易感性。到目前为止，NHP2 突变仅在两名患有 DC 的患者中报道过。在这里，我们报告了首例由 NHP2 双等位基因突变引起的严重形式的先天性角化不良（Høyeraal-Hreidarsson 综合征）的病例。此外，我们还发现了三名携带 NHP2 杂合突变的 PF 无关患者。值得注意的是，其中一名患者获得了 TERT 启动子的体细胞突变，这可能在血液细胞的亚群中赋予了选择性优势。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，我们的研究结果拓宽了 NHP2 缺乏的功能后果和临床谱。
