Common and Rare Variants in TMEM175 Gene Concur to the Pathogenesis of Parkinson's Disease in Italian Patients.

Autor: Palomba NP; IRCCS INM Neuromed, Pozzilli, IS, Italy., Fortunato G; Institute of Genetics and Biophysics, Adriano Buzzati-Traverso', National Research Council, Naples, Italy.; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania Luigi Vanvitelli, Caserta, Italy., Pepe G; IRCCS INM Neuromed, Pozzilli, IS, Italy., Modugno N; IRCCS INM Neuromed, Pozzilli, IS, Italy., Pietracupa S; IRCCS INM Neuromed, Pozzilli, IS, Italy., Damiano I; Institute of Genetics and Biophysics, Adriano Buzzati-Traverso', National Research Council, Naples, Italy., Mascio G; IRCCS INM Neuromed, Pozzilli, IS, Italy., Carrillo F; Institute of Genetics and Biophysics, Adriano Buzzati-Traverso', National Research Council, Naples, Italy., Di Giovannantonio LG; Institute of Genetics and Biophysics, Adriano Buzzati-Traverso', National Research Council, Naples, Italy., Ianiro L; IRCCS INM Neuromed, Pozzilli, IS, Italy., Martinello K; IRCCS INM Neuromed, Pozzilli, IS, Italy., Volpato V; Dementia Research Institute, Cardiff University, Cardiff, UK., Desiato V; IRCCS INM Neuromed, Pozzilli, IS, Italy., Acri R; IRCCS INM Neuromed, Pozzilli, IS, Italy., Storto M; IRCCS INM Neuromed, Pozzilli, IS, Italy., Nicoletti F; IRCCS INM Neuromed, Pozzilli, IS, Italy.; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy., Webber C; Dementia Research Institute, Cardiff University, Cardiff, UK.; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy, Genetics, University of Oxford, Oxford, UK., Simeone A; Institute of Genetics and Biophysics, Adriano Buzzati-Traverso', National Research Council, Naples, Italy., Fucile S; IRCCS INM Neuromed, Pozzilli, IS, Italy.; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy., Maglione V; IRCCS INM Neuromed, Pozzilli, IS, Italy., Esposito T; IRCCS INM Neuromed, Pozzilli, IS, Italy. teresa.esposito@igb.cnr.it.; Institute of Genetics and Biophysics, Adriano Buzzati-Traverso', National Research Council, Naples, Italy. teresa.esposito@igb.cnr.it.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2023 Apr; Vol. 60 (4), pp. 2150-2173. Date of Electronic Publication: 2023 Jan 07.
DOI: 10.1007/s12035-022-03203-9
Abstrakt: Parkinson's disease (PD) represents the most common neurodegenerative movement disorder. We recently identified 16 novel genes associated with PD. In this study, we focused the attention on the common and rare variants identified in the lysosomal K + channel TMEM175. The study includes a detailed clinical and genetic analysis of 400 cases and 300 controls. Molecular studies were performed on patient-derived fibroblasts. The functional properties of the mutant channels were assessed by patch-clamp technique and co-immunoprecipitation. We have found that TMEM175 was highly expressed in dopaminergic neurons of the substantia nigra pars compacta and in microglia of the cerebral cortex of the human brain. Four common variants were associated with PD, including two novel variants rs2290402 (c.-10C > T) and rs80114247 (c.T1022C, p.M341T), located in the Kozak consensus sequence and TM3II domain, respectively. We also disclosed 13 novel highly penetrant detrimental mutations in the TMEM175 gene associated with PD. At least nine of these mutations (p.R35C, p. R183X, p.A270T, p.P308L, p.S348L, p. L405V, p.R414W, p.P427fs, p.R481W) may be sufficient to cause the disease, and the presence of mutations of other genes correlated with an earlier disease onset. In vitro functional analysis of the ion channel encoded by the mutated TMEM175 gene revealed a loss of the K + conductance and a reduced channel affinity for Akt. Moreover, we observed an impaired autophagic/lysosomal proteolytic flux and an increase expression of unfolded protein response markers in patient-derived fibroblasts. These data suggest that mutations in TMEM175 gene may contribute to the pathophysiology of PD.
(© 2023. The Author(s).)
Databáze: MEDLINE
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