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TMEM230: How does it fit in the etiology and pathogenesis of Parkinson's disease?
Wim Mandemakers1, Marialuisa Quadri1, Maria Stamelou2,3
1Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
Abstract:
Mutations in the transmembrane protein 230 (TMEM230) gene were recently identified in a large Canadian pedigree and 7 smaller Chinese families, nominating TMEM230 as the third gene causing a Mendelian form of late onset Parkinson's disease (PD) with typical Lewy-body pathology (after synuclein alpha (SNCA) and leucine rich repeat kinase 2 (LRRK2)). The protein encoded by TMEM230 remains largely uncharacterized, but initial evidence points to roles in the trafficking of recycling vesicles, retromers, and endosomes, suggesting intriguing links to the pathways targeted by other PD-causing genes. The focus on family-based studies is gaining new momentum in the next-generation sequencing era, for the discovery of further, high-penetrance (medically relevant) genetic variants in PD. However, at this junction, important aspects of the TMEM230 story remain unclear, such as the prevalence of these mutations in the Chinese and other populations of the world, the penetrance of the mutations, and even their mode of inheritance. The first replication studies among Chinese and White PD patients have been largely negative. Furthermore, much more work remains ahead to elucidate the mechanisms by which these mutations might lead to neuronal cell death, alpha-synuclein pathology, and parkinsonism. © 2017 International Parkinson and Movement Disorder Society.
Insights
Mutations in the transmembrane protein 230 (TMEM230) gene are linked to a rare form of Parkinson's disease (PD). Further research is needed to understand TMEM230's role and mutation prevalence in diverse populations.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Mutations in transmembrane protein 230 (TMEM230) have been identified in families with Mendelian late-onset Parkinson's disease (PD).
- TMEM230 is implicated in vesicle trafficking, connecting it to pathways affected by other known PD-associated genes like SNCA and LRRK2.
- Family-based studies using next-generation sequencing are crucial for discovering high-penetrance genetic variants in PD.
Purpose of the Study:
- To investigate the role of TMEM230 mutations in Parkinson's disease pathogenesis.
- To explore the prevalence and penetrance of TMEM230 mutations in different global populations.
- To elucidate the molecular mechanisms underlying TMEM230-associated neurodegeneration and alpha-synuclein pathology.
Main Methods:
- Genetic analysis of pedigrees to identify TMEM230 mutations.
- Functional studies to characterize TMEM230 protein and its cellular functions.
- Population-based studies to assess mutation prevalence and penetrance.
Main Results:
- TMEM230 mutations were initially found in Canadian and Chinese families with PD.
- Replication studies in Chinese and White PD patients yielded largely negative results.
- The precise function of TMEM230 and the exact mechanisms of associated neurodegeneration remain largely uncharacterized.
Conclusions:
- TMEM230 is a candidate gene for a rare Mendelian form of Parkinson's disease.
- Significant knowledge gaps exist regarding TMEM230 mutation prevalence, penetrance, and inheritance patterns.
- Further research is essential to understand TMEM230's function and its contribution to PD pathology.
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