https://scholars.lib.ntu.edu.tw/handle/123456789/626456
標題: | A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome | 作者: | Chu, Chia-Mei HSIN-HUI YU Kao, Tsai-Ling Chen, Yi-Hsuan Lu, Hsuan-Hsuan EN-TING WU Yang, Yun-Li CHIN-HSIEN LIN SHIN-YU LIN Tsai, Meng-Ju Melody YIN-HSIU CHIEN WUH-LIANG HWU WEN-PIN CHEN NI-CHUNG LEE CHI-KANG TSENG |
公開日期: | 30-十月-2022 | 卷: | 7 | 期: | 1 | 來源出版物: | NPJ genomic medicine | 摘要: | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/626456 | ISSN: | 2056-7944 | DOI: | 10.1038/s41525-022-00335-8 |
顯示於: | 醫學系 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。