A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome

Hoyeraal-Hreidarsson syndrome (HHS) is the most severe form of dyskeratosis congenita (DC) and is caused by mutations in genes involved in telomere maintenance. Here, we identified male siblings from a family with HHS carrying a hemizygous mutation located in the C-terminal nuclear localization signal (NLS) of the DKC1 gene. These patients exhibit progressive cerebellar hypoplasia, recurrent infections, pancytopenia due to bone marrow failure, and short leukocyte telomere lengths. Single-cell RNA sequencing analysis suggested defects in the NLRP3 inflammasome in monocytes and the activation and maturation of NK cells and B cells. In experiments using induced pluripotent stem cells (iPSCs) from patients, DKC1_R449G iPSCs had short telomere lengths due to reduced levels of human telomerase RNA (hTR) and increased cytosolic proportions of DKC1. Treatment with dihydroquinolizinone RG7834 and 3 deoxyanosine cordycepin rescued telomere length in patient-derived iPSCs. Together, our findings not only provide new insights into immunodeficiency in DC patients but also provide treatment options for telomerase insufficiency disorders.

霍伊拉尔-赖德松综合征（Hoyeraal-Hreidarsson syndrome, HHS）是先天性角化不良（dyskeratosis congenita, DC）最严重的亚型，其发病与参与端粒维持（telomere maintenance）的基因突变密切相关。本研究在一个携带半合子突变（hemizygous mutation）的HHS家系中鉴定出两名男性同胞患者，该突变位于DKC1基因的C端核定位信号（nuclear localization signal, NLS）区域。该类患者表现为进行性小脑发育不全、反复感染、骨髓衰竭引发的全血细胞减少症，以及白细胞端粒长度缩短。单细胞RNA测序（single-cell RNA sequencing）分析显示，患者单核细胞中的NLRP3炎症小体（NLRP3 inflammasome）存在功能缺陷，且自然杀伤细胞（natural killer cell, NK细胞）与B细胞的活化及成熟过程异常。利用患者来源的诱导多能干细胞（induced pluripotent stem cells, iPSCs）开展的实验表明，DKC1_R449G型iPSCs中人端粒酶RNA（human telomerase RNA, hTR）水平降低，且DKC1蛋白的胞质占比升高，进而导致端粒长度缩短。经二氢喹啉酮RG7834与3-脱氧腺苷虫草素处理后，患者来源iPSCs的端粒长度得以恢复。综上，本研究不仅为先天性角化不良患者的免疫缺陷机制提供了全新见解，也为端粒酶功能不足类疾病开辟了潜在治疗途径。