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Published on: December 31, 2013
Reviewing critical TRPM2 variants through a structure-function lens
1Department of Biochemistry, Semmelweis University, 37-47 Tűzoltó street, Budapest 1094, Hungary; HCEMM-SE Molecular Channelopathies Research Group, 37-47 Tűzoltó street, Budapest 1094, Hungary; HUN-REN-SE Ion Channel Research Group, 37-47 Tűzoltó street, Budapest 1094, Hungary.
Abstract:
The transient receptor potential melastatin 2 (TRPM2) channel plays a central role in connecting redox state with calcium signaling in living cells. This coupling makes TRPM2 essential for physiological functions such as pancreatic insulin secretion or cytokine production, but also allows it to contribute to pathological processes, including neuronal cell death or ischemia-reperfusion injury. Genetic deletion of the channel, albeit not lethal, alters physiological functions in mice. In humans, population genetic studies and whole-exome sequencing have identified several common and rare genetic variants associated with mental disorders and neurodegenerative diseases, including single nucleotide variants (SNVs) in exonic regions. In this review, we summarize available information on the four best-documented SNVs: one common (rs1556314) and three rare genetic variants (rs139554968, rs35288229, and rs145947009), manifested in amino acid substitutions D543E, R707C, R755C, and P1018L respectively. We discuss existing evidence supporting or refuting the associations between SNVs and disease. Furthermore, we aim to interpret the molecular impacts of these amino acid substitutions based on recently published structures of human TRPM2. Finally, we formulate testable hypotheses and suggest means to investigate them. Studying the function of proteins with rare mutations might provide insight into disease etiology and delineate new drug targets.
Insights
Transient Receptor Potential Melastatin 2 (TRPM2) channels link cell redox state to calcium signaling. This review examines TRPM2 genetic variants and their potential roles in neurodegenerative diseases and mental disorders.
Area of Science:
- Molecular Biology
- Cell Physiology
- Genetics
Background:
- The TRPM2 channel is crucial for linking cellular redox state to calcium signaling.
- TRPM2 is implicated in both normal physiological processes and diseases like neuronal cell death and ischemia-reperfusion injury.
- Genetic variations in TRPM2 are associated with mental and neurodegenerative disorders in humans.
Purpose of the Study:
- To review documented single nucleotide variants (SNVs) in the TRPM2 gene.
- To discuss evidence linking these SNVs to disease associations.
- To interpret the molecular impact of amino acid substitutions caused by these SNVs using structural data.
Main Methods:
- Literature review of genetic studies and exome sequencing data.
- Analysis of four well-documented TRPM2 SNVs (rs1556314, rs139554968, rs35288229, rs145947009).
- Interpretation of amino acid substitutions (D543E, R707C, R755C, P1018L) based on human TRPM2 structures.
Main Results:
- Identified one common and three rare TRPM2 SNVs associated with potential disease links.
- Examined evidence for and against the association of these variants with specific diseases.
- Provided molecular interpretations of the functional consequences of these amino acid changes.
Conclusions:
- Studying TRPM2 variants, especially rare ones, can offer insights into disease mechanisms.
- TRPM2 mutations may represent novel therapeutic targets for neurological and psychiatric conditions.
- Further research is needed to validate these hypotheses and explore therapeutic potential.
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