{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T08:12:15Z","timestamp":1783152735789,"version":"3.54.6"},"posted":{"date-parts":[[2025,8,31]]},"group-title":"Neuroscience","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,31]],"date-time":"2025-08-31T00:00:00Z","timestamp":1756598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH\/NINDS","award":["1R01NS134816-01"],"award-info":[{"award-number":["1R01NS134816-01"]}]},{"name":"NIH","award":["T34 GM136493"],"award-info":[{"award-number":["T34 GM136493"]}]},{"name":"Southeastern Conference (SEC) Scholar"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth type 2S (CMT2S) are due to mutations in immunoglobulin mu binding protein two (\n                  <jats:italic>IGHMBP2<\/jats:italic>\n                  ). We generated the\n                  <jats:italic>Ighmbp2<\/jats:italic>\n                  -R604X mouse (R605X-humans) to understand how alterations in IGHMBP2 function impact disease pathology. The IGHMBP2-R605X mutation is associated with patients with SMARD1 or CMT2S. The impact of this mutation is substantial,\n                  <jats:italic>Ighmbp2<\/jats:italic>\n                  <jats:sup>R604X\/R604X<\/jats:sup>\n                  mice have a decreased lifespan (6 days) and weight, and failure to thrive consistent with SMARD1 symptoms. Significant respiratory changes were present along with disease pathology of the phrenic nerve and diaphragm muscle fibers.\n                  <jats:italic>Ighmbp2<\/jats:italic>\n                  <jats:sup>R604X\/R604X<\/jats:sup>\n                  mice also presented with signs of milk aspiration and lung pathology. Interestingly,\n                  <jats:italic>Ighmbp2<\/jats:italic>\n                  <jats:sup>R604X\/R604X<\/jats:sup>\n                  mice were born with visible milk spots, but demonstrated reduction of the milk spot by P3, indicating deficits in suckling. Alterations in hindlimb electrophysiology were consistent with the sciatic nerve, hindlimb neuromuscular junction and muscle pathology. Injection of the ssAAV9-WT-\n                  <jats:italic>IGHMBP2<\/jats:italic>\n                  vector extended\n                  <jats:italic>Ighmbp2<\/jats:italic>\n                  <jats:sup>R604X\/R604X<\/jats:sup>\n                  survival a few days, due to reduced expression of the vector before death ensued.\n                  <jats:italic>Ighmbp2<\/jats:italic>\n                  <jats:sup>R604X\/R604X<\/jats:sup>\n                  phenotypes are consistent with the most severe SMARD1 clinical symptoms and for the first time a\n                  <jats:italic>Ighmbp2<\/jats:italic>\n                  mouse model demonstrates that milk aspiration and loss of the ability to suckle impact survival.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"672633v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.27.672633","type":"posted-content","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T05:50:13Z","timestamp":1756705813000},"source":"Crossref","is-referenced-by-count":1,"title":["The\n                  <i>Ighmbp2<\/i>\n                  -R604X mouse recapitulates the severe SMARD1 clinical symptoms of aspiration, respiratory and feeding deficits"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9006-5283","authenticated-orcid":false,"given":"F. Javier Llorente","family":"Torres","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxanne","family":"Muchow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3902-9984","authenticated-orcid":false,"given":"Michelle","family":"Woolridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5504-2409","authenticated-orcid":false,"given":"Dennis","family":"Perez-Lopez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole L.","family":"Nichols","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1023-2169","authenticated-orcid":false,"given":"Christian L.","family":"Lorson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1772-0712","authenticated-orcid":false,"given":"Monique A.","family":"Lorson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025090401300747000_2025.08.27.672633v1.1","doi-asserted-by":"publisher","DOI":"10.1086\/302636"},{"key":"2025090401300747000_2025.08.27.672633v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10182"},{"key":"2025090401300747000_2025.08.27.672633v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/ng703"},{"key":"2025090401300747000_2025.08.27.672633v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20525"},{"key":"2025090401300747000_2025.08.27.672633v1.5","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-820994"},{"issue":"1-2","key":"2025090401300747000_2025.08.27.672633v1.6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jns.2014.09.010","article-title":"The wide spectrum of clinical phenotypes of spinal muscular atrophy with respiratory distress type 1: a systematic review","volume":"346","year":"2014","journal-title":"J Neurol Sci"},{"key":"2025090401300747000_2025.08.27.672633v1.7","doi-asserted-by":"publisher","DOI":"10.1177\/0883073807310989"},{"key":"2025090401300747000_2025.08.27.672633v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.10.002"},{"issue":"5","key":"2025090401300747000_2025.08.27.672633v1.9","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1212\/WNL.0000000000001220","article-title":"Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy","volume":"84","year":"2015","journal-title":"Neurology"},{"issue":"10","key":"2025090401300747000_2025.08.27.672633v1.10","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.nmd.2015.07.017","article-title":"Autosomal recessive axonal polyneuropathy in a sibling pair due to a novel homozygous mutation in IGHMBP2","volume":"25","year":"2015","journal-title":"Neuromuscul Disord"},{"issue":"2","key":"2025090401300747000_2025.08.27.672633v1.11","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.nmd.2016.11.008","article-title":"IGHMBP2-related clinical and genetic features in a cohort of Chinese Charcot-Marie-Tooth disease type 2 patients","volume":"27","year":"2017","journal-title":"Neuromuscul Disord"},{"key":"2025090401300747000_2025.08.27.672633v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.20.10928"},{"key":"2025090401300747000_2025.08.27.672633v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00628-5"},{"key":"2025090401300747000_2025.08.27.672633v1.14","doi-asserted-by":"publisher","DOI":"10.1086\/421054"},{"key":"2025090401300747000_2025.08.27.672633v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/ng1303"},{"key":"2025090401300747000_2025.08.27.672633v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp028"},{"key":"2025090401300747000_2025.08.27.672633v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2010.03.011"},{"key":"2025090401300747000_2025.08.27.672633v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(96)00630-0"},{"key":"2025090401300747000_2025.08.27.672633v1.19","doi-asserted-by":"crossref","unstructured":"Vadla GP , et al. 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