Not enough by half: NFAT5 haploinsufficiency in two patients with Epstein-Barr virus susceptibility

Abstract

IntroductionThe transcription factor Nuclear factor of activated T cells 5 (NFAT5), pivotal in immune regulation and function, can be induced by osmotic stress and tonicity-independent signals.ObjectiveWe aimed to investigate and characterize two unrelated patients with Epstein-Barr virus susceptibility and no known genetic etiology.MethodsAfter informed consent, we reviewed the electronic charts, extracted genomic DNA, performed whole-exome sequencing, filtered, and prioritized their variants, and confirmed through Sanger sequencing, family segregation analysis, and some functional assays, including lymphoproliferation, cytotoxicity, and characterization of natural killer cells.ResultsWe describe two cases of pediatric Mexican patients with rare heterozygous missense variants in NFAT5 and EBV susceptibility, a school-age girl with chronic-active infection of the liver and bowel, and a teenage boy who died of hemophagocytic lymphohistiocytosis.DiscussionNFAT5 is an important regulator of the immune response. NFAT5 haploinsufficiency has been described as an immunodeficiency syndrome affecting both innate and adaptive immunity. EBV susceptibility might be another manifestation in the spectrum of this disease.

NFAT5 Restricts Bovine Herpesvirus 1 Productive Infection in MDBK Cell Cultures

“…Similarly, it has been reported that NFAT5 inhibits CVB3 replication partially via enhancing expression of inducible nitric oxide synthase (iNOS) ( 29 ), providing a sample that supports our speculations. Interestingly, when starting to prepare our manuscript, one paper was published, which reported that NFAT5 haploinsufficiency may potentially correlate with Epstein-Barr virus (EBV, also called human gammaherpesvirus 4) susceptibility as observed in two patients ( 18 ), indicating that NFAT5 may restrict EBV infection in vivo , as observed in BoHV-1 productive infection in vitro . Together with these reports, antiviral effects of NFAT5 may universally apply to broad spectrum of viruses, including herpesvirus.…”

“…Subsequent studies indicated that NFAT5 was a ubiquitous transcription factor widely expressed in various tissues with pleiotropic functions, such as embryonic development, and cell differentiation ( 11 , 12 ). As an important regulator of both innate and adaptive immunity, NFAT5 is also implicated in the pathogenesis of various diseases, including various inflammatory diseases and cancer development ( 13 – 18 ).…”