{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T06:11:02Z","timestamp":1775628662199,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neural Circuits"],"abstract":"<jats:p>\n                    Hereditary sensory and autonomic neuropathies (HSANs) are a group of recessive genetic disorders affecting the sensory and autonomic components of the peripheral nervous system (PNS). Compared with somatosensory dysfunctions, the pathogenesis of visceral dysfunction in HSANs remains understudied. This study investigated the neural circuit mechanisms underlying the arrhythmias observed in conditional Dystonin (\n                    <jats:italic>Dst<\/jats:italic>\n                    ) gene-trap mice, an animal model of HSAN type VI (HSAN-VI) in which Cre recombinase inactivates\n                    <jats:italic>Dst<\/jats:italic>\n                    expression in selective neural circuits. Inactivation of the\n                    <jats:italic>Dst<\/jats:italic>\n                    gene in PNS neurons using\n                    <jats:italic>Advillin-Cre<\/jats:italic>\n                    caused the degeneration of sensory and sympathetic ganglionic neurons. This was accompanied by arrhythmia, characterized by increased heart rate variability and irregular pulse frequency, which was prominent under isoflurane anesthesia and occurred in the absence of protein aggregate cardiomyopathy. Furthermore, selective inactivation of the\n                    <jats:italic>Dst<\/jats:italic>\n                    gene in PNS sensory neurons using\n                    <jats:italic>Vglut2-Cre<\/jats:italic>\n                    resulted in similar dysregulation of cardiac rhythm. These findings suggest that arrhythmias caused by\n                    <jats:italic>Dst<\/jats:italic>\n                    mutations arise from the disruption of visceral afferent circuits, and that these neural circuits could be potential therapeutic targets for visceral dysfunction in HSAN-VI.\n                  <\/jats:p>","DOI":"10.3389\/fncir.2026.1777115","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:33:36Z","timestamp":1775626416000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Disruption of afferent neural circuits leads to arrhythmia in the animal model of hereditary sensory and autonomic neuropathy 6"],"prefix":"10.3389","volume":"20","author":[{"given":"Nozomu","family":"Yoshioka","sequence":"first","affiliation":[{"name":"Department of Anatomy, School of Life Dentistry at Niigata, Nippon Dental University","place":["Niigata, Japan"]},{"name":"Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University","place":["Niigata, Japan"]},{"name":"Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Graduate School of Medical and Dental Sciences, Niigata University","place":["Niigata, Japan"]},{"name":"Division of Functional Morphology, Department of Anatomy, Iwate Medical University","place":["Iwate, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masayuki","family":"Kurose","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Dentistry, Iwate Medical University","place":["Iwate, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuki","family":"Tainaka","sequence":"additional","affiliation":[{"name":"Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University","place":["Niigata, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takako","family":"Ichiki","sequence":"additional","affiliation":[{"name":"Division of Oral Biochemistry, Graduate School of Medical and Dental Sciences, Niigata University","place":["Niigata, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yousuke","family":"Tsuneoka","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Toho University","place":["Tokyo, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromasa","family":"Funato","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Toho University","place":["Tokyo, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaki","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University","place":["Niigata, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayato","family":"Ohshima","sequence":"additional","affiliation":[{"name":"Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Graduate School of Medical and Dental Sciences, Niigata University","place":["Niigata, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ikuo","family":"Kageyama","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Life Dentistry at Niigata, Nippon Dental University","place":["Niigata, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirohide","family":"Takebayashi","sequence":"additional","affiliation":[{"name":"Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University","place":["Niigata, Japan"]},{"name":"Center for Anatomical Studies, Graduate School of Medicine, Kyoto University","place":["Kyoto, Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"6815","DOI":"10.1007\/s10072-025-08424-z","article-title":"Rare autosomal recessive hereditary sensory and autonomic neuropathy type VI in a Pakistani family caused by a novel DST variant","volume":"46","author":"Ahmad","year":"2025","journal-title":"Neurol. Sci."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1523\/JNEUROSCI.22-04-01303.2002","article-title":"Small proline-rich repeat protein 1A is expressed by axotomized neurons and promotes axonal outgrowth","volume":"22","author":"Bonilla","year":"2002","journal-title":"J. Neurosci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e11627","DOI":"10.7554\/eLife.11627","article-title":"Loss of the transcription factor Meis1 prevents sympathetic neurons target-field innervation and increases susceptibility to sudden cardiac death","volume":"5","author":"Bouilloux","year":"2016","journal-title":"eLife"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/ng0795-301","article-title":"The mouse dystonia musculorum gene is a neural isoform of bullous pemphigoid antigen 1","volume":"10","author":"Brown","year":"1995","journal-title":"Nat. Genet."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.cell.2015.03.022","article-title":"Vagal sensory neuron subtypes that differentially control breathing","volume":"161","author":"Chang","year":"2015","journal-title":"Cell"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"e2253232024","DOI":"10.1523\/JNEUROSCI.2253-23.2024","article-title":"ELP1, the gene mutated in familial Dysautonomia, is required for Normal enteric nervous system development and maintenance and for gut epithelium homeostasis","volume":"44","author":"Chaverra","year":"2024","journal-title":"J. Neurosci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"959815","DOI":"10.3389\/fcvm.2022.959815","article-title":"Convergent cardiorespiratory neurons represent a significant portion of cardiac and respiratory neurons in the vagal ganglia","volume":"5","author":"Devarajan","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1093\/brain\/87.2.367","article-title":"Clinical and pathological studies of a hereditary neuropathy in mice (dystonia musculorum)","volume":"87","author":"Duchen","year":"1964","journal-title":"Brain"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1002\/ana.23524","article-title":"Hereditary sensory autonomic neuropathy caused by a mutation in dystonin","volume":"71","author":"Edvardson","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2694","DOI":"10.1093\/hmg\/ddt663","article-title":"Transgenic expression of neuronal dystonin isoform 2 partially rescues the disease phenotype of the dystonia musculorum mouse model of hereditary sensory autonomic neuropathy VI","volume":"23","author":"Ferrier","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/0092-8674(95)90333-x","article-title":"Gene targeting of BPAG1: abnormalities in mechanical strength and cell migration in stratified epithelia and neurologic degeneration","volume":"81","author":"Guo","year":"1995","journal-title":"Cell"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"14404","DOI":"10.1523\/JNEUROSCI.4908-07.2007","article-title":"Analyzing somatosensory axon projections with the sensory neuron-specific Advillin gene","volume":"27","author":"Hasegawa","year":"2007","journal-title":"J. Neurosci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.nbd.2016.09.016","article-title":"Characterization of novel dystonia musculorum mutant mice: implications for central nervous system abnormality","volume":"96","author":"Horie","year":"2016","journal-title":"Neurobiol. 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Int."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"ENEURO.0077-18.2018","DOI":"10.1523\/ENEURO.0077-18.2018","article-title":"Advillin is expressed in all adult neural crest-derived neurons","volume":"5","author":"Hunter","year":"2018","journal-title":"eNeuro"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.neuroscience.2005.08.081","article-title":"The survival of vagal and glossopharyngeal sensory neurons is dependent upon dystonin","volume":"137","author":"Ichikawa","year":"2006","journal-title":"Neuroscience"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1038\/s41586-021-04359-5","article-title":"Sensory representation and detection mechanisms of gut osmolality change","volume":"602","author":"Ichiki","year":"2022","journal-title":"Nature"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"2452","DOI":"10.1242\/dev.107797","article-title":"A neuron autonomous role for the familial dysautonomia gene ELP1 in sympathetic and sensory target tissue innervation","volume":"141","author":"Jackson","year":"2014","journal-title":"Development"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"awaf227","DOI":"10.1093\/brain\/awaf227","article-title":"Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital myopathy","volume":"149","author":"Jacob","year":"2025","journal-title":"Brain"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/bmt.2012.244","article-title":"Investigation of the freely available easy-to-use software \u2018EZR\u2019 for medical statistics","volume":"48","author":"Kanda","year":"2013","journal-title":"Bone Marrow Transplant."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/s0168-0102(02)00009-3","article-title":"Complementary distribution of vesicular glutamate transporters in the central nervous system","volume":"42","author":"Kaneko","year":"2002","journal-title":"Neurosci. Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1097\/00000542-199210000-00009","article-title":"Spectral analysis of heart rate variability during isoflurane anesthesia","volume":"77","author":"Kato","year":"1992","journal-title":"Anesthesiology"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"28331","DOI":"10.1038\/srep28331","article-title":"Mitochondrial fission is an acute and adaptive response in injured motor neurons","volume":"6","author":"Kiryu-Seo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1111\/exd.12877","article-title":"One gene but different proteins and diseases: the complexity of dystonin and bullous pemphigoid antigen 1","volume":"25","author":"K\u00fcnzli","year":"2016","journal-title":"Exp. Dermatol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"e13773","DOI":"10.1111\/nmo.13773","article-title":"Characterization of gastrointestinal pathologies in the dystonia musculorum mouse model for hereditary sensory and autonomic neuropathy type VI","volume":"32","author":"Lynch-Godrei","year":"2020","journal-title":"Neurogastroenterol. Motil."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat. 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Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"3659","DOI":"10.1523\/JNEUROSCI.2134-21.2022","article-title":"Thoracic VGluT2+ spinal interneurons regulate structural and functional plasticity of sympathetic networks after high-level spinal cord injury","volume":"42","author":"Noble","year":"2022","journal-title":"J. Neurosci."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1016\/j.neuron.2021.12.020","article-title":"Internal senses of the vagus nerve","volume":"110","author":"Prescott","year":"2022","journal-title":"Neuron"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1944","DOI":"10.1038\/s41467-019-09770-1","article-title":"Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies","volume":"10","author":"Rajendran","year":"2019","journal-title":"Nat. Commun."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/nrneurol.2011.227","article-title":"Mechanisms of disease in hereditary sensory and autonomic neuropathies","volume":"8","author":"Rotthier","year":"2012","journal-title":"Nat. Rev. Neurol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1034\/j.1600-0404.2001.00051.x","article-title":"Adult-onset hereditary sensory and autonomic neuropathy accompanied by anosmia but without skin ulceration","volume":"104","author":"Sakae","year":"2001","journal-title":"Acta Neurol. Scand."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"7221","DOI":"10.1073\/pnas.0502273102","article-title":"Genomewide production of multipurpose alleles for the functional analysis of the mouse genome","volume":"102","author":"Schn\u00fctgen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1152\/physrev.00018.2022","article-title":"The enteric nervous system","volume":"103","author":"Sharkey","year":"2023","journal-title":"Physiol. Rev."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2196","DOI":"10.1016\/j.celrep.2018.07.056","article-title":"Chemical landscape for tissue clearing based on hydrophilic reagents","volume":"24","author":"Tainaka","year":"2018","journal-title":"Cell Rep."},{"key":"ref41","first-page":"2412","article-title":"Injury-specific expression of activating transcription factor-3 in retinal ganglion cells and its colocalized expression with phosphorylated c-Jun","volume":"41","author":"Takeda","year":"2000","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"46620","DOI":"10.1038\/srep46620","article-title":"MEIS1 variant as a determinant of autonomic imbalance in restless legs syndrome","volume":"7","author":"Thireau","year":"2017","journal-title":"Sci. Rep."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1006\/mcne.1999.0814","article-title":"Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: a novel neuronal marker of nerve injury","volume":"15","author":"Tsujino","year":"2000","journal-title":"Mol. Cell. Neurosci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.neuron.2011.05.028","article-title":"Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons","volume":"71","author":"Vong","year":"2011","journal-title":"Neuron"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1038\/s41575-018-0062-1","article-title":"The metabolic role of vagal afferent innervation","volume":"15","author":"Waise","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s12565-023-00739-1","article-title":"Roles of dystonin isoforms in the maintenance of neural, muscle, and cutaneous tissues","volume":"99","author":"Yoshioka","year":"2024","journal-title":"Anat. Sci. Int."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1242\/dmm.041608","article-title":"Diverse dystonin gene mutations cause distinct patterns of Dst isoform deficiency and phenotypic heterogeneity in dystonia musculorum mice","volume":"13","author":"Yoshioka","year":"2020","journal-title":"Dis. Model. Mech."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1126\/sciadv.adj9335","article-title":"Sensory-motor circuit is a therapeutic target for dystonia musculorum mice, a model of hereditary sensory and autonomic neuropathy 6","volume":"10","author":"Yoshioka","year":"2024","journal-title":"Sci. Adv."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"e78419","DOI":"10.7554\/eLife.78419","article-title":"Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy","volume":"11","author":"Yoshioka","year":"2022","journal-title":"eLife"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"9424","DOI":"10.1073\/pnas.0914725107","article-title":"Deletion of PIK3C3\/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway","volume":"107","author":"Zhou","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/1744-8069-7-66","article-title":"Generation and characterization of an Advillin-Cre driver mouse line","volume":"7","author":"Zurborg","year":"2011","journal-title":"Mol. 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