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 (c.1345C > G, p.R449G), 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.

Hoyeraal-Hreidarsson 综合征 (HHS) 是最严重的先天性角化不良 (DC)，由参与端粒维持的基因突变引起。在这里，我们鉴定出来自 HHS 家族的男性兄弟姐妹携带半合子突变（c.1345C >G，p.R449G），该突变位于DKC1基因的 C 端核定位信号 (NLS)。这些患者表现出进行性小脑发育不全、反复感染、骨髓衰竭引起的全血细胞减少以及白细胞端粒长度短。单细胞 RNA 测序分析表明单核细胞中的 NLRP3 炎性体以及 NK 细胞和 B 细胞的激活和成熟存在缺陷。在使用来自患者的诱导多能干细胞 (iPSC) 的实验中，由于人端粒酶 RNA (hTR) 水平降低和 DKC1 胞质比例增加，DKC1_R449G iPSC 的端粒长度较短。使用二氢喹嗪酮 RG7834 和 3'脱氧肌苷虫草素治疗可恢复患者来源 iPSC 的端粒长度。总之，我们的研究结果不仅为 DC 患者的免疫缺陷提供了新的见解，而且还为端粒酶不足性疾病提供了治疗选择。