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

Abstract

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.