Evidence for contribution of compound heterozygous variants in Wiskott-Aldrich syndrome like (WASL) gene for early onset Parkinson’s disease

Abstract

AbstractBackgroundKnowledge of genetic determinants in Parkinson’s disease is still limited. Familial forms of the disease continue to provide a rich resource to capture the genetic spectrum in disease pathogenesis, and this approach has been exploited in this study.MethodsInformative members from a three-generation family of Indian ethnicity manifesting a likely autosomal recessive mode of inheritance of PD were used for whole exome sequencing. Variant data analysis and in vitro functional characterisation of putative disease causal variant(s) identified thereof were carried out in HEK-293 and SH-SY5Y cells using gene constructs of interest.ResultsIn a rather uncommon observation, two compound heterozygous variants, a rare missense (c.1139C>T:p.P380L) and a novel splice variant (c.1456+5TAGAG>G) in Wiskott-Aldrich syndrome like gene (WASL, 7q31), both predicted to be deleterious were shared among the proband and her two affected siblings. WASL, a gene hitherto unreported for PD is known to regulate actin polymerisation via Arp2/3 complex. Based on exon trapping assay using pSPL3 vector in HEK-293 cells, the splice variant showed skipping of exon10. Functional characterisation of the missense variant in SH-SY5Y cells demonstrated: i) significant alterations in neurite length and number; ii) decreased ROS tolerance in mutation carrying cells on TBPH induction, and iii) increase in alpha-synuclein protein. Screening for WASL variants in two independent PD cohorts identified four individuals with heterozygous but none with biallelic variants.ConclusionWASL, with demonstrated functional relevance in neurons may be yet another putative disease causal gene for autosomal recessive PD encouraging assessment of its contribution across populations.