FINCA disease mouse model exhibits altered behaviour and immune response

Abstract

Fibrosis, neurodegeneration and cerebral angiomatosis (FINCA) is a childhood-onset multi-organ neurodevelopmental disorder associated with multi-organ manifestations and recurrent infections. The disease is caused by variants in NHLRC2 initiating a cascade of unknown pathological events. Previously, we have demonstrated that despite the significant decrease at the molecular level, the compound heterozygosity of knock out and p.Asp148Tyr alleles in NHLRC2 does not lead to a severe phenotype in mice. Here, we analysed the behavioural and immunological phenotype of the FINCA mice and studied the molecular pathways affected by p.Asp148Tyr in NHLRC2 using mouse and human-derived cell culture models. The FINCA mice displayed a mild hyperactivity and deficient early immune response when challenged with LPS leading to altered cytokine responses, including IFN{gamma}, IL-12, and TNF. By comparing gene expression and putative interaction partners affected by p.Asp148Tyr, we identified Rho GTPase signalling as the common pathway. Altogether, these results establish a multi-dimensional impact of the p.Asp148Tyr variant in NHLRC2. Knowledge of the molecular pathways affected by NHLRC2 and the natural course of FINCA disease progression are instrumental for the development of effective therapeutics. Summary statementFINCA is a paediatric neurodevelopmental and multi-organ disorder caused by variants in NHLRC2. Here, mild hyperactivity in connection with altered early immune response is described in the FINCA mouse model.