Genetic analysis of TMEM230 variants in Han Chinese patients with Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, and gait disturbance. The transmembrane protein 230 gene (TMEM230) was initially identified as a disease-causing gene in autosomal dominant PD while the role of TMEM230 in PD remains controversial. This study investigated the genetic role of TMEM230 variants in PD. Whole exome sequencing and Sanger sequencing were performed on a cohort of 518 unrelated PD patients (388 sporadic and 130 familial) and 539 age- and sex-matched controls. Identified TMEM230 variants were analyzed based on frequency assessments, bioinformatics prediction tools, and conservation analysis. The three-dimensional structures of the wild-type and mutated proteins were modeled using SWISS-MODEL and Missense3D, with visualization using PyMOL. Statistical analysis was performed to evaluate the association between TMEM230 variants and PD. Eight rare heterozygous TMEM230 variants were identified in sporadic PD patients and controls, including seven missense variants and a synonymous variant. Bioinformatics prediction analyses suggested that p.Gly16Trp and p.Arg23Gln were likely to have a damaging role, supporting their potential involvement in PD pathogenesis. The prevalence of TMEM230 missense variants was significantly higher in PD cases compared to controls (1.93 % vs. 0.37 %, P = 0.017, odds ratio = 5.29, 95 % confidence interval: 1.15-24.24). This study enhances the understanding of the genetic landscape of TMEM230 in the Han Chinese PD population and implies that TMEM230 may function as an autosomal dominant disease-causing gene of PD with low penetrance, or as a susceptibility gene, though the pathogenicity of TMEM230 variants is warranted by further investigation.