Short Qt Syndrome and Sudden Cardiac Death Due to a Mutation in the Tmem175 Endolysosomal Potassium Channel

Jáimez, Juan Jiménez; Bermúdez, F.J. Brenes; Moreno-Manuel, Ana I.; Monteros, Lilian Gutiérrez Espinosa de los; Vera-Pedrosa, María Linarejos; Álvarez, Miguel; Tercedor, Luís

doi:10.1016/s0735-1097(20)31096-2

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“…Other SNPs of TMEM175 were shown to be associated with early-onset and late-onset PD [103,104]. Genome-wide association studies and mutation analysis have identified important SNPs of TMEM175 in many other diseases such as type 2 diabetes [105], breast cancer [106], systemic sclerosis [107], Lewy body dementia [108], and short QT syndrome [109] (Table 2). However, the functional role of TMEM175 in these diseases remains unclear.…”

Section: Snps Of Tmem175 In Other Diseasesmentioning

confidence: 99%

Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson’s Disease

2023

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Lysosomes are membrane-bound organelles with an acidic lumen and are traditionally characterized as a recycling center in cells. Lysosomal ion channels are integral membrane proteins that form pores in lysosomal membranes and allow the influx and efflux of essential ions. Transmembrane protein 175 (TMEM175) is a unique lysosomal potassium channel that shares little sequence similarity with other potassium channels. It is found in bacteria, archaea, and animals. The prokaryotic TMEM175 consists of one six-transmembrane domain that adopts a tetrameric architecture, while the mammalian TMEM175 is comprised of two six-transmembrane domains that function as a dimer in lysosomal membranes. Previous studies have demonstrated that the lysosomal K+ conductance mediated by TMEM175 is critical for setting membrane potential, maintaining pH stability, and regulating lysosome–autophagosome fusion. AKT and B-cell lymphoma 2 regulate TMEM175’s channel activity through direct binding. Two recent studies reported that the human TMEM175 is also a proton-selective channel under normal lysosomal pH (4.5–5.5) as the K+ permeation dramatically decreased at low pH while the H+ current through TMEM175 greatly increased. Genome-wide association studies and functional studies in mouse models have established that TMEM175 is implicated in the pathogenesis of Parkinson’s disease, which sparks more research interests in this lysosomal channel.

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