Age-dependent impairment of dopamine D1 receptor signalling in mouse striatum by variant P626L.

Non-coding CGG repeat expansions in () gene lead to fragile X-related disorders. Other than the CGG repeat expansion, several coding variants have recently been identified to impair the molecular functions of fragile X messenger ribonucleoprotein 1 (FMRP), implicating in FMR1-associated phenotypes. This study aims to investigate the pathogenic role of a novel missense variant from a parkinsonism patient without the typical CGG repeat expansion. Pathogenicity of the FMRP-P626L mutant was predicted using analysis and structural prediction. A mouse model of FMRP-P608L mutation matched with the human FMRP-P626L was established. The effects on dopamine pathway in FMRP-P608L mice were investigated using behavioural test, immunohistochemistry, ELISA, quantitative PCR (qPCR), western blotting, co-immunoprecipitation and pharmacological intervention. We identified a missense variant (c.1877 C>T, p.P626L) in coding region of gene from a patient diagnosed with progressive rigidity and bradykinesia, which was predicted to be a damaging mutation. The corresponding mutation (P608L) mice at 6 months old exhibited impaired motor behaviours and decreased in striatal dopamine level in an age-dependent fashion. The mutant reduced FMRP binding to G protein-coupled receptor kinase 2 (GRK2), which resulted in abnormal localization of GRK2 and impairment of dopamine D1 receptor (D1R) pathways. Administration of D1R agonist rescued the motor disabilities observed in the mutation mice. This is the first report linking a point mutation in to parkinsonism, demonstrating that the FMRP-P608L mutation impairs the D1R pathway by reducing its binding to GRK2. Our findings enhance the understanding of pathogenic mechanisms underlying selective functional impairment by mutations.