Natural Killer Cell Deficiency in Neuroblastoma Amplified Sequence Gene Mutation

Jia³

et al. 2023

Hum Genome Var

Mutations in the neuroblastoma amplified sequence (NBAS) gene correlate with infantile acute liver failure (ALF). Herein, we identified a novel NBAS mutation in a female infant diagnosed with recurrent ALF. Whole-exome and Sanger sequencing revealed that the proband carried a compound heterozygous mutation (c.938_939delGC and c.1342 T > C in NBAS). NBAS c.938_939delGC was presumed to encode a truncated protein without normal function, whereas NBAS c.1342 T > C encoded NBAS harboring the conserved Cys448 residue mutated to Arg448 (p.C448R). The proportion of CD4 + T cells decreased in the patient’s peripheral CD45 + cells, whereas that of CD8 + T cells increased. Moreover, upon transfecting the same amount of DNA expression vector (ectopic expression) encoding wild-type NBAS and p.C448R NBAS, the group transfected with the p.C448R NBAS-expressing vector expressed less NBAS mRNA and protein. Furthermore, ectopic expression of the same amount of p.C448R NBAS protein as the wild-type resulted in more intracellular reactive oxygen species and the induction of apoptosis and expression of marker proteins correlating with endoplasmic reticulum stress in more cultured cells. This study indicated that p.C448R NBAS has a function different from that of wild-type NBAS and that the p.C448R NBAS mutation potentially affects T-cell function and correlates with ALF.

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

A novel variant in NBAS identified from an infant with fever-triggered recurrent acute liver failure disrupts the function of the gene

Jia³

et al. 2023

Hum Genome Var

“…We also found that the NBAS C448R mutation could be linked to immunode ciencies. Mutations in the NBAS gene have previously been linked to immunode ciencies, 21,22 with general symptoms of NBASlinked immunode ciencies including decreased immunoglobulin G levels, CD56 + NK, and CD19 + naive B cells. 21,23 However, our patient displayed normal IgG levels in another study, 20 and we believe that NBAS dysfunction also changed T cell homeostasis (Fig.…”

Section: Discussionmentioning

confidence: 99%

Role of a novel neuroblastoma amplified sequence mutation, c.1342T>C (p.Cys448Arg), in an infant with fever-triggered recurrent acute liver failure

Chu

et al. 2022

Preprint

Mutations localized in the neuroblastoma amplified sequence (NBAS) gene correlate with infantile liver failure syndrome 2. In this study, we identified a novel NBAS mutation in a 26-month-old Chinese female diagnosed with fever-triggered recurrent acute liver failure (ALF). The proband exhibited highly elevated liver enzymes, severe coagulopathy, and acute renal failure. Whole-exome and Sanger sequencing revealed that the proband carried a compound heterozygous missense mutation in NBAS c.938_939delGC and c.1342T > C (p.Cys448Arg), the former of which causes a truncated NBAS protein without normal function and the latter of which affects evolutionarily conserved amino acid residues. The ratio of peripheral CD3+, CD4+, and CD45 + to CD3+, CD8+, and CD45 + cells was lower in the patient than in children without ALF. Moreover, the c.1342T > C mutation reduced the expression of NBAS mRNA and protein, enriched intracellular reactive oxygen species, and induced cell apoptosis and endoplasmic reticulum stress in in vitro cell models. Our study clarifies the mechanism by which NBAS mutations regulate ALF progression. Furthermore, we suggest employing NBAS gene detection in children with unexplained fever-triggered recurrent ALF or liver dysfunction.

“…We also supported that this NBAS C448R mutation could be linked to immunode ciencies. The mutations in NBAS gene has been linked to immunode ciencies in several literatures [19,20]. The general symptoms of NBAS-linked immunode ciencies were shown to be decreased immunoglobulin G levels, CD56 + NK and CD19 + naive B cells [19,21].…”

Section: Discussionmentioning

confidence: 99%

A novel mutation, c.1342T>C (p.Cys448Arg) identified from an infant with fever-triggered recurrent acute liver failure, affects expressions of NBAS mRNA and protein and induces cellular stress in vitro

JunJun³

et al. 2022

Preprint

The mutations in neuroblastoma amplified sequence (NBAS) gene correlate with two clinical spectra: short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome and infantile liver failure syndrome 2 (ILFS2). Here, we describe a study of a 26-month-old Chinese girl who was diagnosed with fever-triggered recurrent acute liver failure (ALF). The clinical characteristics were great elevation of liver enzymes, severe coagulopathy, and acute renal failure. Whole-exome and Sanger sequencing of the patient and his parents revealed that she carried novel compound heterozygous missense mutations in NBAS c.938_939delGC and c.1342T > C (p.Cys448Arg). The frameshift mutation c.[938_939delGC] should cause truncated NBAS protein without normal function and c.1342T > C (p.Cys448Arg) mutation affects evolutionarily conserved amino acid residues. And we found the ratio of peripheral CD3+CD4+CD45+ to CD3+CD8+CD45+ was lower in patient than that in normal children, and c.1342T > C mutation reduced expression of NBAS mRNA and protein, enriched intracellular reactive oxygen species, and induced cell apoptosis and endoplasmic reticulum stress in vitro cell models. Our study would enrich our understanding of the mechanism of NBAS mutation in regulating the ALF progress. We recommend NBAS gene analysis in children with unexplained fever-triggered recurrent ALF or liver dysfunction.