TY - JOUR
T1 - NBAS, a gene involved in cytotoxic degranulation, is recurrently mutated in pediatric hemophagocytic lymphohistiocytosis
AU - Bi, Xiaoman
AU - Zhang, Qing
AU - Chen, Lei
AU - Liu, Dan
AU - Li, Yueying
AU - Zhao, Xiaoxi
AU - Zhang, Ya
AU - Zhang, Liping
AU - Liu, Jingkun
AU - Wu, Chaoyi
AU - Li, Zhigang
AU - Zhao, Yunze
AU - Ma, Honghao
AU - Huang, Gang
AU - Liu, Xin
AU - Wang, Qian fei
AU - Zhang, Rui
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Germline variants
KW - Hemophagocytic lymphohistiocytosis
KW - NBAS
KW - NK-cell
KW - Trios
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U2 - 10.1186/s13045-022-01318-z
DO - 10.1186/s13045-022-01318-z
M3 - Letter
C2 - 35902954
AN - SCOPUS:85135190326
SN - 1756-8722
VL - 15
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 101
ER -