A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome
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...
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| Format: | Article |
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Nature Portfolio
2022-10-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-022-00335-8 |
| _version_ | 1811192399582461952 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chia-Mei Chu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T23:52:05Z |
| format | Article |
| id | doaj.art-9aecb9637b0d4a5bbbfe6204b5fa8c01 |
| institution | Directory Open Access Journal |
| issn | 2056-7944 |
| language | English |
| last_indexed | 2024-04-11T23:52:05Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj.art-9aecb9637b0d4a5bbbfe6204b5fa8c012022-12-22T03:56:28ZengNature Portfolionpj Genomic Medicine2056-79442022-10-017111210.1038/s41525-022-00335-8A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndromeChia-Mei Chu0Hsin-Hui Yu1Tsai-Ling Kao2Yi-Hsuan Chen3Hsuan-Hsuan Lu4En-Ting Wu5Yun-Li Yang6Chin-Hsien Lin7Shin-Yu Lin8Meng-Ju Melody Tsai9Yin-Hsiu Chien10Wuh-Liang Hwu11Wen-Pin Chen12Ni-Chung Lee13Chi-Kang Tseng14Department of Microbiology, College of Medicine, National Taiwan UniversityDepartment of Pediatrics National Taiwan University Children’s Hospital TaipeiDepartment of Microbiology, College of Medicine, National Taiwan UniversityCenter for Frontier Medicine, National Taiwan University HospitalCenter for Frontier Medicine, National Taiwan University HospitalDepartment of Pediatrics National Taiwan University Children’s Hospital TaipeiDepartment of Pediatrics National Taiwan University Children’s Hospital TaipeiDepartment of Neurology, National Taiwan University HospitalDepatment of Obstetrics and Gynecology, National Taiwan University HospitalDepartment of Pediatrics National Taiwan University Children’s Hospital TaipeiDepartment of Pediatrics National Taiwan University Children’s Hospital TaipeiDepartment of Pediatrics National Taiwan University Children’s Hospital TaipeiInstitute of Pharmacology, College of Medicine, National Taiwan UniversityDepartment of Pediatrics National Taiwan University Children’s Hospital TaipeiDepartment of Microbiology, College of Medicine, National Taiwan UniversityAbstract 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.https://doi.org/10.1038/s41525-022-00335-8 |
| spellingShingle | 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 A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome npj Genomic Medicine |
| title | A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome |
| title_full | A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome |
| title_fullStr | A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome |
| title_full_unstemmed | A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome |
| title_short | A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome |
| title_sort | missense variant in the nuclear localization signal of dkc1 causes hoyeraal hreidarsson syndrome |
| url | https://doi.org/10.1038/s41525-022-00335-8 |
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