NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis

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

doi:10.1186/s13045-022-01318-z

NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis

J Hematol Oncol. 2022 Jul 28;15(1):101. doi: 10.1186/s13045-022-01318-z.

Authors

Xiaoman Bi^#^{1

2

3

4}, Qing Zhang^#⁵, Lei Chen^#^{1

2

3}, Dan Liu^{1

2}, Yueying Li^{1

2}, Xiaoxi Zhao⁵, Ya Zhang^{1

2

3}, Liping Zhang⁶, Jingkun Liu^{1

2

3}, Chaoyi Wu^{1

2

3}, Zhigang Li⁵, Yunze Zhao⁶, Honghao Ma⁶, Gang Huang⁷, Xin Liu^{8

9

10}, Qian-Fei Wang^{11

12

13}, Rui Zhang¹⁴

Affiliations

¹ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China.
² China National Center for Bioinformation, Beijing, 100045, China.
³ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁴ Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou, 571199, China.
⁵ Hematologic 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 Health, Beijing, 100045, China.
⁶ 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 Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
⁷ Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
⁸ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. liuxin@big.ac.cn.
⁹ China National Center for Bioinformation, Beijing, 100045, China. liuxin@big.ac.cn.
¹⁰ University of Chinese Academy of Sciences, Beijing, 100049, China. liuxin@big.ac.cn.
¹¹ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. wangqf@big.ac.cn.
¹² China National Center for Bioinformation, Beijing, 100045, China. wangqf@big.ac.cn.
¹³ University of Chinese Academy of Sciences, Beijing, 100049, China. wangqf@big.ac.cn.
¹⁴ 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 Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China. ruizh1973@126.com.

^# Contributed equally.

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.

Keywords: Germline variants; Hemophagocytic lymphohistiocytosis; NBAS; NK-cell; Trios.

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Child
Cohort Studies
Humans
Killer Cells, Natural / metabolism
Lymphohistiocytosis, Hemophagocytic* / diagnosis
Lymphohistiocytosis, Hemophagocytic* / genetics
Mutation
Neoplasm Proteins
T-Lymphocytes, Cytotoxic

Substances

NBAS protein, human
Neoplasm Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding