TMEM230 – Parkinson disease

TMEM230 was first implicated in autosomal dominant Parkinson disease (PD) in a four-generation American family, in which rare variants segregated with Lewy body–confirmed PD (PMID:27872751). However, subsequent sequencing efforts in diverse populations have not supported a major role for TMEM230 in PD etiology: no pathogenic variants were identified in 550 sporadic PD patients and 560 controls (PMID:28446760), in young-onset PD cohorts (PMID:28709721), in Taiwanese familial and sporadic cases (PMID:28766910), in Caucasian series (PMID:27818000), or in a southern Spanish cohort (PMID:29771939). A large Chinese case-control study recently reported three rare damaging TMEM230 variants in PD patients (versus none in controls) but did not demonstrate statistical significance after correction (PMID:35860667). Collectively, genetic evidence remains limited to a single pedigree with no robust replication.

Despite sparse genetic validation, functional studies provide moderate support for a pathogenic role. In primary mouse neurons and HEK293 cells, PD-linked TMEM230 variants impaired synaptic vesicle trafficking and elevated α-synuclein levels (PMID:27872751). The c.233G>T (p.Arg78Leu) mutant showed reduced protein stability without interacting with LRRK2 (PMID:30460091); other PD-associated mutants triggered PARP1-linked apoptosis (PMID:32848711) and disrupted retrograde axonal mitochondrial transport (PMID:34002226). These data suggest a dominant gain-of-function mechanism perturbing vesicular and mitochondrial dynamics. At present, TMEM230 testing offers limited diagnostic yield, yet functional concordance indicates pathogenic potential and warrants further genetic investigation.

References

• Journal of clinical movement disorders • 2016 • Novel gene (TMEM230) linked to Parkinson's disease. PMID:27872751
• Neurobiology of aging • 2017 • Screening for TMEM230 mutations in young-onset Parkinson's disease. PMID:28709721
• American journal of medical genetics. Part B, Neuropsychiatric genetics • 2017 • Lack of TMEM230 mutations in patients with familial and sporadic Parkinson's disease in a Taiwanese population. PMID:28766910
• Neurobiology of aging • 2017 • Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population. PMID:27818000
• PloS one • 2018 • TMEM230 in Parkinson's disease in a southern Spanish population. PMID:29771939
• Scientific reports • 2017 • Genetic analysis of the TMEM230 gene in Chinese Han patients with Parkinson's disease. PMID:28446760
• Frontiers in aging neuroscience • 2022 • Genetic Analysis of Six Transmembrane Protein Family Genes in Parkinson's Disease in a Large Chinese Cohort. PMID:35860667
• Animal cells and systems • 2018 • Characterization of Parkinson's disease-related pathogenic TMEM230 mutants. PMID:30460091
• Frontiers in aging neuroscience • 2020 • Transmembrane Protein 230 Mediates a Poly(ADP-ribose) Polymerase-1-Linked Apoptosis. PMID:32848711
• Human molecular genetics • 2021 • Mutant-TMEM230-induced neurodegeneration and impaired axonal mitochondrial transport. PMID:34002226

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