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

Chia-Mei Chu; Hsin-Hui Yu; Tsai-Ling Kao; Yi-Hsuan Chen; Hsuan-Hsuan Lu; En-Ting Wu; Yun-Li Yang; Chin-Hsien Lin; Shin-Yu Lin; Meng-Ju Melody Tsai; Yin-Hsiu Chien; Wuh-Liang Hwu; Wen-Pin Chen; Ni-Chung Lee; Chi-Kang Tseng

doi:10.1038/s41525-022-00335-8

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

NPJ Genom Med. 2022 Oct 30;7(1):64. doi: 10.1038/s41525-022-00335-8.

Authors

Chia-Mei Chu^#¹, Hsin-Hui Yu^#², Tsai-Ling Kao¹, Yi-Hsuan Chen³, Hsuan-Hsuan Lu³, En-Ting Wu², Yun-Li Yang², Chin-Hsien Lin⁴, Shin-Yu Lin⁵, Meng-Ju Melody Tsai², Yin-Hsiu Chien^{2

6}, Wuh-Liang Hwu^{2

6}, Wen-Pin Chen⁷, Ni-Chung Lee^{8

9}, Chi-Kang Tseng¹⁰

Affiliations

¹ Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Pediatrics National Taiwan University Children's Hospital Taipei, Taipei, Taiwan.
³ Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁴ Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Depatment of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
⁷ Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei City, Taiwan.
⁸ Department of Pediatrics National Taiwan University Children's Hospital Taipei, Taipei, Taiwan. ncleentu@ntu.edu.tw.
⁹ Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan. ncleentu@ntu.edu.tw.
¹⁰ Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan. ckt0513@ntu.edu.tw.

^# Contributed equally.

Abstract

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.