NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis
Abstract Hemophagocytic lymphohistiocytosis (HLH), particularly primary HLH (pHLH), is a rare, life-threatening disease. Germline genetic deficiency of 12 known HLH genes impairs cytotoxic degranulation in natural killer (NK) cells or cytotoxic T lymphocytes (CTLs) and contributes to pHLH developmen...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-07-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13045-022-01318-z |
| _version_ | 1818492121585287168 |
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| author | Xiaoman Bi Qing Zhang Lei Chen Dan Liu Yueying Li Xiaoxi Zhao Ya Zhang Liping Zhang Jingkun Liu Chaoyi Wu Zhigang Li Yunze Zhao Honghao Ma Gang Huang Xin Liu Qian-fei Wang Rui Zhang |
| author_facet | Xiaoman Bi Qing Zhang Lei Chen Dan Liu Yueying Li Xiaoxi Zhao Ya Zhang Liping Zhang Jingkun Liu Chaoyi Wu Zhigang Li Yunze Zhao Honghao Ma Gang Huang Xin Liu Qian-fei Wang Rui Zhang |
| author_sort | Xiaoman Bi |
| collection | DOAJ |
| description | Abstract Hemophagocytic lymphohistiocytosis (HLH), particularly primary HLH (pHLH), is a rare, life-threatening disease. Germline genetic deficiency of 12 known HLH genes impairs cytotoxic degranulation in natural killer (NK) cells or cytotoxic T lymphocytes (CTLs) and contributes to pHLH development. However, no pathogenic mutations in these HLH genes are found in nearly 10% of HLH patients, despite a strong suspicion of pHLH, suggesting that the underlying genetic basis of HLH is still unclear. To discover novel susceptibility genes, we first selected 13 children with ppHLH (presumed primary HLH patients in the absence of detectable known HLH gene variants) and their parents for initial screening. Whole-genome sequencing (WGS) in one trio and whole-exome sequencing (WES) in twelve trios revealed that two ppHLH patients carried biallelic NBAS variants, a gene that is involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport upstream of the degranulation pathway. Additionally, two candidate genes, RAB9B and KLC3, showed a direct relationship with known HLH genes in protein-protein interaction (PPI) network analysis. We analyzed NBAS, RAB9B, KLC3 and known HLH genes in an independent validation cohort of 224 pediatric HLH patients. Only biallelic NBAS variants were identified in three patients who harbored no pathogenic variants in any of the known HLH genes. Functionally, impaired NK-cell cytotoxicity and degranulation were revealed in both NBAS biallelic variant patients and in an NBAS-deficient NK-cell line. Knockdown of NBAS in an NK-cell line (IMC-1) using short hairpin RNA (shRNA) resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus. According to our findings, NBAS is the second most frequently mutated gene (2.11%) in our HLH cohort after PRF1. NBAS deficiency may contribute to the development of HLH via a dysregulated lytic vesicle transport pathway. |
| first_indexed | 2024-12-10T17:39:08Z |
| format | Article |
| id | doaj.art-17275d521ff541b0ae80cca36b929f75 |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-10T17:39:08Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-17275d521ff541b0ae80cca36b929f752022-12-22T01:39:26ZengBMCJournal of Hematology & Oncology1756-87222022-07-011511510.1186/s13045-022-01318-zNBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosisXiaoman Bi0Qing Zhang1Lei Chen2Dan Liu3Yueying Li4Xiaoxi Zhao5Ya Zhang6Liping Zhang7Jingkun Liu8Chaoyi Wu9Zhigang Li10Yunze Zhao11Honghao Ma12Gang Huang13Xin Liu14Qian-fei Wang15Rui Zhang16CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesHematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesHematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesHematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesHematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthHematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthHematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDivisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical CenterCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesCAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of SciencesHematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthAbstract Hemophagocytic lymphohistiocytosis (HLH), particularly primary HLH (pHLH), is a rare, life-threatening disease. Germline genetic deficiency of 12 known HLH genes impairs cytotoxic degranulation in natural killer (NK) cells or cytotoxic T lymphocytes (CTLs) and contributes to pHLH development. However, no pathogenic mutations in these HLH genes are found in nearly 10% of HLH patients, despite a strong suspicion of pHLH, suggesting that the underlying genetic basis of HLH is still unclear. To discover novel susceptibility genes, we first selected 13 children with ppHLH (presumed primary HLH patients in the absence of detectable known HLH gene variants) and their parents for initial screening. Whole-genome sequencing (WGS) in one trio and whole-exome sequencing (WES) in twelve trios revealed that two ppHLH patients carried biallelic NBAS variants, a gene that is involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport upstream of the degranulation pathway. Additionally, two candidate genes, RAB9B and KLC3, showed a direct relationship with known HLH genes in protein-protein interaction (PPI) network analysis. We analyzed NBAS, RAB9B, KLC3 and known HLH genes in an independent validation cohort of 224 pediatric HLH patients. Only biallelic NBAS variants were identified in three patients who harbored no pathogenic variants in any of the known HLH genes. Functionally, impaired NK-cell cytotoxicity and degranulation were revealed in both NBAS biallelic variant patients and in an NBAS-deficient NK-cell line. Knockdown of NBAS in an NK-cell line (IMC-1) using short hairpin RNA (shRNA) resulted in loss of lytic granule polarization and a decreased number of cytotoxic vesicles near the Golgi apparatus. According to our findings, NBAS is the second most frequently mutated gene (2.11%) in our HLH cohort after PRF1. NBAS deficiency may contribute to the development of HLH via a dysregulated lytic vesicle transport pathway.https://doi.org/10.1186/s13045-022-01318-zHemophagocytic lymphohistiocytosisGermline variantsTriosNBASNK-cell |
| spellingShingle | Xiaoman Bi Qing Zhang Lei Chen Dan Liu Yueying Li Xiaoxi Zhao Ya Zhang Liping Zhang Jingkun Liu Chaoyi Wu Zhigang Li Yunze Zhao Honghao Ma Gang Huang Xin Liu Qian-fei Wang Rui Zhang NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis Journal of Hematology & Oncology Hemophagocytic lymphohistiocytosis Germline variants Trios NBAS NK-cell |
| title | NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis |
| title_full | NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis |
| title_fullStr | NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis |
| title_full_unstemmed | NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis |
| title_short | NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis |
| title_sort | nbas a gene involved in cytotoxic degranulation is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis |
| topic | Hemophagocytic lymphohistiocytosis Germline variants Trios NBAS NK-cell |
| url | https://doi.org/10.1186/s13045-022-01318-z |
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