A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptors
IntroductionAnxiety disorders are among the most common mental illnesses in the US. An estimated 31.1% of U.S. adults experience any anxiety disorder at some time in their lives. Understanding some of the molecular underpinnings of anxiety could lead to improved treatments over current strategies fo...
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Frontiers Media S.A.
2024-12-01
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| author | Kristin R. Anderson Wenpeng Cao Hui Sun Lee Mark A. Crenshaw Talulla B. Palumbo Ethan Fisher-Perez Amanda DeGraaf Peter Rogu Maria A. Beatty Gabrielle M. Gracias Gabrielle M. Gracias Avani V. Pisapati Katie Hoffman Krystle J. McLaughlin Almut Hupbach Wonpil Im Wonpil Im X. Frank Zhang Julie M. Miwa |
| author_facet | Kristin R. Anderson Wenpeng Cao Hui Sun Lee Mark A. Crenshaw Talulla B. Palumbo Ethan Fisher-Perez Amanda DeGraaf Peter Rogu Maria A. Beatty Gabrielle M. Gracias Gabrielle M. Gracias Avani V. Pisapati Katie Hoffman Krystle J. McLaughlin Almut Hupbach Wonpil Im Wonpil Im X. Frank Zhang Julie M. Miwa |
| author_sort | Kristin R. Anderson |
| collection | DOAJ |
| description | IntroductionAnxiety disorders are among the most common mental illnesses in the US. An estimated 31.1% of U.S. adults experience any anxiety disorder at some time in their lives. Understanding some of the molecular underpinnings of anxiety could lead to improved treatments over current strategies focusing on symptom relief rather than root causes. One significant neurotransmitter system exerting control over anxiety is the nicotinic receptor subdivision of the cholinergic system. The murine Lynx2 gene, encoding a protein modulator of nicotinic acetylcholine receptors, is expressed in anxiety-related neural circuitry in rodents and has been functionally associated with anxiety-like behavior.MethodsWe examined variations in the human LYNX2 (LYPD1) gene and their potential effects on anxiety levels in a cohort of 624 participants. Participants completed validated anxiety questionnaires (e.g., STICSA and STAI), which assessed both their current anxiety and their general tendency to experience anxiety. Possible functional alterations due to one such mutation was assessed through atomic force microscopy (AFM) and computational modeling.ResultsWe identified a previously unreported single nucleotide polymorphism (SNP) in the mature protein-coding region of LYNX2 that was associated with significantly higher than normal anxiety scores. These elevated scores resembled those seen in patients clinically diagnosed with generalized anxiety disorder and panic disorder, although this genetically defined subpopulation did not typically report such diagnoses. Through computational modeling of the homopentameric α7 nicotinic receptor subtype and in vitro atomic force microscopy (AFM), we discovered that a specific LYNX2 SNP is linked to a reduced binding affinity between the LYNX2 protein and nAChRs, offering a potential functional explanation for the role that this mutation may play in anxiety.DiscussionA polymorphism in LYNX2, which codes for an inhibitory modulator of nicotinic acetylcholine receptors, has the potential to lead to sensitized nicotinic receptor activity in anxiety-related circuits. The LYNX2 protein has been shown to bind to multiple nicotinic acetylcholine receptor subtypes, including α4β2, α7, and α3β4 subtypes, each of which have been shown to be involved in affective behaviors. This work suggests that a subpopulation of individuals harboring a deleterious mutation in LYNX2 may predispose them to anxiety through abnormal nicotinic receptor control. In the future, this work may lead to the development of a biomarker for anxiety or a diagnostic tool for the early detection of individuals with susceptibility to anxiety. |
| format | Article |
| id | doaj-art-9518f5d64f6644dfa69bfe01bd7690cd |
| institution | OA Journals |
| issn | 1662-5153 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Behavioral Neuroscience |
| spelling | doaj-art-9518f5d64f6644dfa69bfe01bd7690cd2025-08-20T01:59:51ZengFrontiers Media S.A.Frontiers in Behavioral Neuroscience1662-51532024-12-011810.3389/fnbeh.2024.13475431347543A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptorsKristin R. Anderson0Wenpeng Cao1Hui Sun Lee2Mark A. Crenshaw3Talulla B. Palumbo4Ethan Fisher-Perez5Amanda DeGraaf6Peter Rogu7Maria A. Beatty8Gabrielle M. Gracias9Gabrielle M. Gracias10Avani V. Pisapati11Katie Hoffman12Krystle J. McLaughlin13Almut Hupbach14Wonpil Im15Wonpil Im16X. Frank Zhang17Julie M. Miwa18Department of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Bioengineering, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesBS, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, United StatesDepartment of Bioengineering, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Psychology, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesDepartment of Bioengineering, Lehigh University, Bethlehem, PA, United StatesDepartment of Bioengineering, Lehigh University, Bethlehem, PA, United StatesDepartment of Biological Sciences, Lehigh University, Bethlehem, PA, United StatesIntroductionAnxiety disorders are among the most common mental illnesses in the US. An estimated 31.1% of U.S. adults experience any anxiety disorder at some time in their lives. Understanding some of the molecular underpinnings of anxiety could lead to improved treatments over current strategies focusing on symptom relief rather than root causes. One significant neurotransmitter system exerting control over anxiety is the nicotinic receptor subdivision of the cholinergic system. The murine Lynx2 gene, encoding a protein modulator of nicotinic acetylcholine receptors, is expressed in anxiety-related neural circuitry in rodents and has been functionally associated with anxiety-like behavior.MethodsWe examined variations in the human LYNX2 (LYPD1) gene and their potential effects on anxiety levels in a cohort of 624 participants. Participants completed validated anxiety questionnaires (e.g., STICSA and STAI), which assessed both their current anxiety and their general tendency to experience anxiety. Possible functional alterations due to one such mutation was assessed through atomic force microscopy (AFM) and computational modeling.ResultsWe identified a previously unreported single nucleotide polymorphism (SNP) in the mature protein-coding region of LYNX2 that was associated with significantly higher than normal anxiety scores. These elevated scores resembled those seen in patients clinically diagnosed with generalized anxiety disorder and panic disorder, although this genetically defined subpopulation did not typically report such diagnoses. Through computational modeling of the homopentameric α7 nicotinic receptor subtype and in vitro atomic force microscopy (AFM), we discovered that a specific LYNX2 SNP is linked to a reduced binding affinity between the LYNX2 protein and nAChRs, offering a potential functional explanation for the role that this mutation may play in anxiety.DiscussionA polymorphism in LYNX2, which codes for an inhibitory modulator of nicotinic acetylcholine receptors, has the potential to lead to sensitized nicotinic receptor activity in anxiety-related circuits. The LYNX2 protein has been shown to bind to multiple nicotinic acetylcholine receptor subtypes, including α4β2, α7, and α3β4 subtypes, each of which have been shown to be involved in affective behaviors. This work suggests that a subpopulation of individuals harboring a deleterious mutation in LYNX2 may predispose them to anxiety through abnormal nicotinic receptor control. In the future, this work may lead to the development of a biomarker for anxiety or a diagnostic tool for the early detection of individuals with susceptibility to anxiety.https://www.frontiersin.org/articles/10.3389/fnbeh.2024.1347543/fullLynx2LYPD1nicotinic acetylcholine receptorsanxiety disordershuman psychologyhuman DNA analysis |
| spellingShingle | Kristin R. Anderson Wenpeng Cao Hui Sun Lee Mark A. Crenshaw Talulla B. Palumbo Ethan Fisher-Perez Amanda DeGraaf Peter Rogu Maria A. Beatty Gabrielle M. Gracias Gabrielle M. Gracias Avani V. Pisapati Katie Hoffman Krystle J. McLaughlin Almut Hupbach Wonpil Im Wonpil Im X. Frank Zhang Julie M. Miwa A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptors Frontiers in Behavioral Neuroscience Lynx2 LYPD1 nicotinic acetylcholine receptors anxiety disorders human psychology human DNA analysis |
| title | A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptors |
| title_full | A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptors |
| title_fullStr | A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptors |
| title_full_unstemmed | A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptors |
| title_short | A novel anxiety-associated SNP identified in LYNX2 (LYPD1) is associated with decreased protein binding to nicotinic acetylcholine receptors |
| title_sort | novel anxiety associated snp identified in lynx2 lypd1 is associated with decreased protein binding to nicotinic acetylcholine receptors |
| topic | Lynx2 LYPD1 nicotinic acetylcholine receptors anxiety disorders human psychology human DNA analysis |
| url | https://www.frontiersin.org/articles/10.3389/fnbeh.2024.1347543/full |
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