A novel MAPK1 variant in a family with complex psychiatric and neurodegenerative clinical phenotype

Neurodegenerative disorders leading to dementia often have multifactorial etiologies, but monogenic causes are occasionally identified. We report a three-generation family with two individuals (mother and son) affected by a non-syndromic psychiatric disorder featuring early-onset cognitive decline. Exome sequencing revealed a novel MAPK1 variant (Y128C), de novo in mother, inherited by her son. Modeling demonstrated that the variant alters a regulatory region known as common docking site. Functional studies in patient’s fibroblasts revealed normal levels of phosphorylated MAPK1/3 (pMAPK1/3) but a reduced pMAPK1/pMAPK3 ratio, consistent with diminished MAPK1 activity. Experiments in C. elegans revealed that the variant conferred partial loss of function, reflected in the developmental and reproductive defects. Given the elevated Tau levels in the proband’s cerebrospinal fluid, we also investigated the MAPK1 variant in a C. elegans model expressing human Tau in neurons and observed that it exacerbated age-dependent neurodegeneration, suggesting a context-dependent role in this process. These findings suggest that the MAPK1 Y128C variant causes a novel adult-onset psychiatric disorder with dementia, distinct from the neurodevelopmental syndrome previously associated with MAPK1 mutations.