Journal of neurogenetics最新文献

{"title":"Extra-synaptic localization of Bruchpilot in association with neurite outgrowth and cell motility in dissociated <i>Drosophila</i> embryonic cell cultures.","authors":"Nobuhiro Yamagata, Nobuhiro Takahashi, Nanon Muto, Takafumi Miki, Atulya Iyengar, Michael Dailey, Chun-Fang Wu","doi":"10.1080/01677063.2026.2730920","DOIUrl":"https://doi.org/10.1080/01677063.2026.2730920","url":null,"abstract":"<p><p>Neurite outgrowth and motility are essential for neuronal development and migration, and they play crucial roles in nervous system formation and axonal regeneration. Cytosolic scaffold proteins are key regulators of these processes, and their dysregulation can lead to neurodevelopmental disorders. In flies, Bruchpilot (Brp), an ortholog of the mammalian active zone scaffold protein ELKS/CAST, is a key factor in synapse formation and maintenance and in neurotransmitter release at chemical synapses. Although mammalian ELKS has been implicated in the growth and motility of both neuronal and non-neuronal cells, the roles of Brp beyond synaptic function remain unclear. Here, we show that Brp contributes to neurite outgrowth and cell motility in dissociated embryonic cell cultures of <i>Drosophila</i>. We detected Brp formed discrete cytoplasmic puncta at early developmental stages in dissociated giant neurons derived from cytokinesis-arrested neuroblasts. During neurite extension and branching, the density of Brp puncta increased over time prior to growth events. Consistently, Brp downregulation impeded cell growth. Brp accumulated in the growth cone, the most motile region of dissociated neurons. Brp was also expressed in non-neuronal cell types, such as highly motile hemocytes, raising the possibility that Brp may have broader context-dependent roles in motile cells. Our findings provide the first evidence of a novel functional link between the Brp scaffold and neuronal growth and cell motility, highlighting the conserved multifunctionality of this scaffold protein.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"1-13"},"PeriodicalIF":1.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine mapping of a putative genomic element that mediates the induction of a male-specific muscle in <i>Drosophila</i>.","authors":"Yuri Nakamura, Tamas Lukacsovich, Kenta Tomihara, Hanqing Liang, Tamás Szlanka, Kosei Sato, Daisuke Yamamoto","doi":"10.1080/01677063.2026.2696088","DOIUrl":"https://doi.org/10.1080/01677063.2026.2696088","url":null,"abstract":"<p><p>The muscle of Lawrence (MOL) is a pair of male-specific longitudinal muscles located below the tergite of the fifth abdominal segment in adult <i>Drosophila melanogaster</i>. For the MOL to form, the innervating motor neuron (MOL-inducing neuron: Mind neuron) must express male-specific products of the <i>fruitless</i> (<i>fru</i>) gene, collectively called FruM. We localized a <i>cis</i>-regulatory element of the <i>fru</i> gene that promotes its expression in the Mind neuron to a short genomic interval lying between -4.3 and -5.7 kb upstream of the distal promotor P1 of the <i>fru</i> gene. Comparisons of the sequences of this genomic interval between <i>D. melanogaster</i>, which carries a single MOL pair and <i>D. subobscura</i>, a distant relative that carries two MOL pairs, revealed five conserved stretches, Boxes A-E, tandemly aligned in a single copy (<i>D. melanogaster</i>) or in duplicate (<i>D. subobscura</i>). The <i>Gal4</i> transgenes carrying Boxes A, B, and E together were able to induce the MOL when used to drive <i>UAS-fruM</i>. Deleting Boxes A, B and E from the genome resulted in loss of the MOL, with occasional formation of vestigial MOL-like muscles. Conversely, reintroducing Boxes A, B, and E into the deletant restored the MOL. We conclude that Boxes A, B, and E comprise a major element that promotes <i>fru</i> expression in the Mind neuron for MOL induction, and we propose to call it the <i><u>c</u>is</i>-<u>e</u>lement for <u>MO</u>L <u>i</u>nduction (ceMOi).</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"1-15"},"PeriodicalIF":1.1,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psilocybin-induced behavioral and cellular effects.","authors":"Albert M Dong, Yi Han, Zheng Xu, Oliver M Schlüter, Xiaojie Huang","doi":"10.1080/01677063.2026.2695462","DOIUrl":"https://doi.org/10.1080/01677063.2026.2695462","url":null,"abstract":"<p><p>Psilocybin, a prominent psychedelic, recently emerged as a potential therapeutic agent for psychiatric disorders, yet the molecular and cellular mechanisms driving its effects remain poorly understood. To address these knowledge gaps, we focused on the nucleus accumbens (NAc), a forebrain region that regulates reward, motivation, and emotion. Systemic administration of psilocybin (3 mg/kg) induced a rapid inhibition of mouse locomotor activities, which was resolved by ∼1 h post-psilocybin treatment. By contrast, psilocybin-induced c-Fos expression in the NAc peaked at ∼6 h in neurons post-treatment and at ∼1.5 h in non-neuronal cells. These temporal profiles suggest that, as an immediate early gene and transcription factor, c-Fos may induce prolonged functional changes in NAc neurons and non-neuronal cells differentially through transcriptional regulation. Finally, to probe for endogenous receptors that may mediate the psilocybin effects, we focused on serotonin 2 A (5-HT_2A) and serotonin 2B (5-HT_2B) receptors. Inhibition of 5-HT_2A receptors (Volinanserin, 0.5 mg/kg) selectively reduced psilocybin-induced c-Fos expression in neurons, whereas inhibition of 5-HT_2B receptors (RS 127445, 0.5 mg/kg) reduced psilocybin-induced c-Fos expression in both neurons and non-neuronal cells. These results suggest that 5-HT_2B receptors and non-neuronal cells may be key players in the regulation of circuits underlying mood-related disorders.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"1-9"},"PeriodicalIF":1.1,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Variants in PLPBP, SCN1A, and SLC6A1: Genetics, Bioinformatics, and clinical Elucidation of Three Distinct Cases of Developmental and Epileptic Encephalopathy.","authors":"Haneieh Honarmand, Sina Babaei, Mortaza Bonyadi, Mohammad Barzegar","doi":"10.1080/01677063.2026.2687566","DOIUrl":"https://doi.org/10.1080/01677063.2026.2687566","url":null,"abstract":"<p><p>Developmental and epileptic encephalopathies (DEEs) are severe early-onset disorders featuring refractory seizures, abnormal EEGs, and developmental delays. Clinically and etiologically heterogeneous, they include subtypes such as Dravet syndrome and EIMFS. An increasing number are recognized as etiology-specific, with distinct genetic causes corresponding to characteristic phenotypes, highlighting the need for thorough diagnostic evaluation. This study utilized a multidisciplinary diagnostic approach to investigate DEE. In this descriptive case series, the reported novel variants include a <i>PLPBP</i> duplication (c.596dup), an <i>SCN1A</i> insertion (c.3879dup), and an <i>SLC6A1</i> in-frame deletion (c.943_945del). Bioinformatics and segregation analysis supported their pathogenicity, with each variant linked to a distinct clinical phenotype. The reported novel variants broaden the phenotypic and genotypic spectrum of these disorders and inform clinical management and genetic counseling.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"1-12"},"PeriodicalIF":1.1,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E-cigarette exposure impairs associative memory: role of α7 and β2 nicotinic acetylcholine receptors.","authors":"Titilayomi Ayomide Otenaike, Oluwabukola Farodoye, Katherina K Silva, Amos O Abolaji, Elgion Lucio Silva Loreto","doi":"10.1080/01677063.2026.2613797","DOIUrl":"10.1080/01677063.2026.2613797","url":null,"abstract":"<p><p>E-cigarettes also known as vape, are rapidly gaining recognition as having potential neurological consequences, yet their neural effects on sensory valence and associative learning remain poorly understood, necessitating urgent investigation into their potential neurocognitive effects. This is particularly important because nicotine, the primary psychoactive component in most vape liquid, acts directly on nicotinic acetylcholine receptors (nAChRs) in the brain. Hence, the role of nAChRs in the control of neural learning and memory in response to this drug is fundamental. Here, we investigated how vape exposure modulates olfactory behaviour, reinforcement processing, and the influence α7 or β2 nicotinic acetylcholine receptors (nAChR) mutation in <i>Drosophila melanogaster</i>. In this study, vape exposure significantly affected motor performance and cholinergic function, as evidenced by altered negative geotaxis and acetylcholinesterase (AChE) activity after chronic treatment with 0.06, 0.08, and 0.12 mg/mL vape in different flies genotypes. Addionally, using a combination of innate odour preference and conditioning assays, we found that wild-type flies displayed an inherent attraction to strawberry odour and avoidance of aversive one (marula). However, exposure to vape altered these intrinsic preferences, reversing attraction to aversion and attenuating innate avoidance exhibited as \"addiction-like\" behaviour in wild-type flies. Notably, these vape-induced shifts in odour valence were abolished in <i>nAChRα7^-/-</i> and <i>nAChRβ2^-/-</i> mutants, implicating nicotinic acetylcholine receptor signaling in mediating nicotine's neuromodulatory effects. However, α7 and β2 significantly differ in odour discrimination and detection of chemically related odour pairs, while β2 nAChR mutants display a strong resistance to learning, further impairing memory performance. Together, our findings indicate that vape acts not merely as an associative cue but as a neuromodulator that reshapes innate sensory valence through α7 and β2-containing nAChRs. This work establishes <i>Drosophila</i> as a powerful genetic model for understanding the neural mechanisms by which vape exposure alters odour valence and reinforcement processing, providing new insight into the addictive properties of vaping.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"35-52"},"PeriodicalIF":1.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Nckx30c</i>, a <i>Drosophila</i> K⁺-dependent Na⁺/Ca²⁺ exchanger, regulates temperature-sensitive convulsions and age-related neurodegeneration.","authors":"Al Nahian Khan Majlish, Sophia Bourgeois, Shu Hui Lye, Saul Landaverde, Emilia Cytron, Megan Cline, Harris Bolus, Robert N Correll, Atulya Iyengar, Stanislava Chtarbanova","doi":"10.1080/01677063.2026.2655158","DOIUrl":"10.1080/01677063.2026.2655158","url":null,"abstract":"<p><p>Calcium (Ca²⁺) homeostasis is fundamental to neuronal physiology, including in the regulation of membrane excitability and synaptic transmission. Disruptions in the ion transporters regulating Ca²⁺ influx and efflux are clearly linked to seizure disorders and age-related neurodegenerative disease. Yet, the specific contributions of variants in genes encoding these transporters to neurological disease remain to be fully understood. <i>Drosophila melanogaster</i> has proven to be a powerful genetic model for uncovering such mechanisms, particularly through studies of mutants that display temperature-sensitive (TS) behavioral phenotypes. In a forward genetic screen, we identified a mutant line that exhibited TS convulsions along with progressive, age-dependent neurodegeneration. We mapped the mutation to <i>Nckx30c</i>, specifically within the transmembrane ion-binding region of this K⁺-dependent Na⁺/Ca²⁺ exchanger. Characterization of this mutant, together with a second <i>Nckx30c</i> allele, revealed TS convulsions, impaired locomotion, a markedly shortened lifespan, neurodegeneration with age, along with structural defects at larval and adult neuromuscular junctions (NMJs). <i>Nckx30c</i> mutants also displayed altered neural motor circuit performance. Gene expression analysis confirmed that <i>Nckx30c</i> levels were reduced in heads of <i>Nckx30c</i> loss-of-function mutants. Tissue-specific manipulation revealed that knockdown of <i>Nckx30c</i> in neurons recapitulated the TS convulsions, locomotor defects, and shortened lifespan phenotypes. <i>Drosophila Nckx30c</i> is highly conserved and shares homology with mammalian <i>SLC24A2</i>, a solute carrier family 24 member whose neurological role is not yet fully elucidated. Our work establishes <i>Nckx30c</i> as an essential regulator of neuronal health and provides an <i>in vivo</i> framework for investigating the contribution of <i>SLC24A2</i> to neuronal Ca²⁺ homeostasis, seizures and age-related neurodegeneration.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"1-24"},"PeriodicalIF":1.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A zinc finger MYM-type containing 3 (ZMYM3) allele is associated with autism spectrum disorder in Iranian people.","authors":"Maryam Razavi, Mobina Tabibian, Zahra Lakpour, Shiva Mehrabi, Maryam Salmanian, Rana Ghamari, Azar Mohammad-Zadeh, Mehdi Tehrani-Doost, Mina Ohadi, Fatemeh Alizadeh","doi":"10.1080/01677063.2026.2636893","DOIUrl":"10.1080/01677063.2026.2636893","url":null,"abstract":"<p><p>Previous studies indicate a link between an exceptionally long GA-repeat in the Zinc finger MYM-type containing 3 (<i>ZMYM3</i>) gene and higher-order brain functions, reflected in human-specific cognitive disorders. Here, we studied this GA-repeat in a cohort of unrelated male subjects, consisting of patients affected by autism spectrum disorder (ASD) (<i>n</i> = 100) and controls (<i>n</i> = 200). We also analyzed pooled samples from this study and previous studies of this GA-repeat in three other major psychiatric disorders (<i>n</i> = 721), including schizophrenia (SCZ), bipolar disorder (BD), and late-onset neurocognitive disorder (NCD) and pooled controls (<i>n</i> = 487). An allele at the extreme short end (17-repeat) was detected in the ASD cases, which was not detected in the control samples (mid-<i>p</i> ≤ 0.05). This allele overlapped with the extreme allele detected in SCZ, BD, and late-onset NCD. Furthermore, we found a significantly different genetic architecture at this locus in the ASD patients vs. pooled controls. In conclusion, we report a significant association between the human <i>ZMYM3</i> 17-repeat allele and ASD, which overlaps with SCZ, BD, and late-onset NCD. Our findings reinforce the hypothesis that low-frequency alleles at the extreme allele lengths at this locus co-occur with a number of major psychiatric disorders and undergo natural selection.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"80-85"},"PeriodicalIF":1.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D-ribose-L-cysteine protects against rotenone-induced neurotoxicity in <i>Drosophila</i> via redox, neurotransmitter, and DDC gene regulation.","authors":"Olumayowa Kolawole Idowu, Adebusola Zainab Sogbesan, Adewale Emmanuel Ajibade, Oluwatomisin Olalekan Faniyan, Omosola Fisayo Anifowose, Tope Gafar Atere, Olufunke Olubusola Dosumu","doi":"10.1080/01677063.2026.2658577","DOIUrl":"10.1080/01677063.2026.2658577","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor dysfunctions. Although the underlying mechanisms are multifactorial, oxidative stress, inflammation, and dopaminergic deficits are central to its pathogenesis. D-Ribose-L-Cysteine (DRLC), a glutathione (GSH) precursor, has shown potential protective effects in models of human diseases. This study investigates the neuroprotective effects of DRLC against rotenone (ROT)-induced PD-like pathology in <i>Drosophila melanogaster</i>. Adult <i>Drosophila</i> (Harwich strain) were segregated into five groups and administered either a control diet, 500 μM ROT, or ROT in conjunction with DRLC (125, 250, or 500 μM) for a duration of 14 days. Longevity, locomotor, and olfactory assays were performed. Biochemical analysis of dissected fly brains assessed redox status markers, pro-inflammatory cytokines, apoptosis indicators, neurotransmitter levels, and dopa-decarboxylase (DDC) gene expression. ROT exposure reduced survival by 25%, significantly impaired motor and olfactory functions, increased reactive oxygen species (ROS) levels, disrupted neurotransmission, elevated TNF-α and caspase-3 levels, and downregulated DDC gene expression. DRLC co-treatment improved survival and motor performance in a dose-dependent manner while also decreasing ROS, TNF-α, and caspase-3 expression. DRLC restored dopamine and acetylcholine levels and GSH concentrations compared to the ROT-only group. DRLC also upregulated DDC gene expression. In conclusion, DRLC mitigates ROT-induced PD-like neurotoxicity in <i>Drosophila</i> through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, possibly via enhanced GSH synthesis and dopamine regulation. Although we cannot fully rule out the possibility that DRLC affected rotenone ingestion or feeding behavior, the fact that ROT-dependent phenotypes persisted in the absence of DRLC and were only selectively reversed by DRLC suggests a neuroprotective effect.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"25-34"},"PeriodicalIF":1.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147981984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic architecture of hereditary spastic paraplegia: from monogenic to oligogenic models.","authors":"Giuseppe Pedullà, Maurizio Morelli, Monica Gagliardi, Radha Procopio, Andrea Quattrone, Enrico Fratto, Antonio Gambardella","doi":"10.1080/01677063.2026.2671912","DOIUrl":"10.1080/01677063.2026.2671912","url":null,"abstract":"<p><p>Hereditary spastic paraplegia (HSP) encompasses a clinically and genetically heterogeneous group of neurodegenerative disorders, characterized by progressive lower limb spasticity due to corticospinal tract degeneration. While traditionally regarded as monogenic, recent genomic advances have revealed more complex inheritance models, including oligogenic and polygenic contributions. This mini-review examines the evolving genetic landscape of HSP, integrating established monogenic forms with emerging evidence of cumulative variant burden. Importantly, current evidence remains insufficient to establish oligogenic inheritance as a validated or broadly applicable pathogenic mechanism in HSP, and most available data should be considered exploratory and hypothesis-generating rather than conclusive. Monogenic subtypes such as SPG4, SPG7, and SPG11 remain central to current understanding, but analyses of large sequencing cohorts show that up to 40% of cases lack a single-gene explanation. Both statistical analyses and illustrative reports, such as ultra-rare variant enrichment involving SYNE1, CAPN1, and PGAP1, suggest that oligogenic inheritance may operate in a subset of unresolved cases, although current evidence remains preliminary and not yet broadly validated. Pathogenic mechanisms converge on shared molecular pathways including microtubule dynamics, endoplasmic reticulum shaping, lipid metabolism, mitochondrial maintenance, and vesicular trafficking. Recognition of these multilayered mechanisms informs diagnostic strategies, favoring whole-exome or genome sequencing, variant burden analysis, and refined genetic counselling. Functional studies in cellular and animal models, coupled with biomarker discovery, are crucial to unravel gene-gene interactions and identify therapeutic targets. HSP exemplifies a genetic continuum ranging from high-penetrance monogenic forms to genetically unresolved phenocopies and putative oligogenic cases influenced by cumulative variant burden. Accordingly, diagnosis should incorporate multi-locus models as a hypothesis-testing framework in selected unresolved cases rather than as an established default explanation, counselling must address probabilistic inheritance, and therapeutic development should prioritize pathway-based interventions. Multidisciplinary integration of genomic, mechanistic, and clinical insights is essential to achieve precise diagnoses and personalized therapies.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"53-59"},"PeriodicalIF":1.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147972911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurocardiogenetics: Exploring the association of rare <i>RYR2</i> variants with neuropsychiatric disorders in general and disease populations.","authors":"Saif F Dababneh, Jason D Roberts, Sixuan Tan, Jinhong Wei, Ruiwu Wang, John Paul Estillore, Dania Kallas, Glen F Tibbits, Shubhayan Sanatani, S R Wayne Chen, Thomas M Roston","doi":"10.1080/01677063.2026.2632080","DOIUrl":"10.1080/01677063.2026.2632080","url":null,"abstract":"<p><p>Overlapping neuropsychiatric and cardiac features in rare monogenic syndromes stem from shared gene expression. Pathogenic gain-of-function <i>RYR2</i> variants, leading to a lethal cardiac arrhythmia syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT), have also been associated with neuropsychiatric disorders such as epilepsy, schizophrenia, and intellectual disability. Neuropsychiatric phenotypes have not been reported in patients with calcium release deficiency syndrome (CRDS), a recently described inherited arrhythmia disorder distinct from CPVT caused by loss-of-function <i>RYR2</i> variants. Whether there is a robust association between ultra-rare <i>RYR2</i> variants and neuropsychiatric phenotypes in large population databases and disease cohorts has not been determined to-date. Here, we explore the association of <i>RYR2</i> variants with neuropsychiatric disorders in 748,879 individuals from multiple biobanks, including 155,236 non-Europeans, and in neuropsychiatric disease cohorts. Our analyses suggest an association between <i>RYR2</i> variants and epilepsy, while links with other disorders were not robust. In this process, a previously uncharacterized <i>RYR2</i> variant (p.Y4962N) with conflicting reported pathogenicity was found to be associated with both cardiac and neuropsychiatric phenotypes. To better understand the potential impact of the variant, we further assessed its mechanistic impact and found that RyR2<i>-</i>p.Y4962N results in loss-of-function. Such a finding has not been reported previously in association with <i>RYR2</i> loss-of-function variants or CRDS. Altogether, our study expands our understanding of the involvement of <i>RYR2</i> variants in neurocardiac phenotypes in general populations and disease cohorts, which could enhance personalized medicine efforts by integrating cardiac and neuropsychiatric risk profiles.</p>","PeriodicalId":16491,"journal":{"name":"Journal of neurogenetics","volume":" ","pages":"86-94"},"PeriodicalIF":1.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147290146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}