{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T09:06:29Z","timestamp":1789722389216,"version":"4.0.1"},"reference-count":39,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":1964,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"funder":[{"name":"University of Alabama at Birmingham Neurofibromatosis Program"},{"DOI":"10.13039\/100002017","name":"Children's Tumor Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002017","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:p>Neurofibromatosis type 1 (NF1) is a common genetic disorder characterized by the occurrence of nerve sheath tumors and considerable clinical heterogeneity. Some translational studies have been limited by the lack of animal models assessing patient-specific mutations. In order to test therapeutic approaches that may restore function to the mutated gene or gene product, we developed mice harboring NF1 patient-specific mutations including a nonsense mutation (c.2041C&amp;gt;T; p.Arg681*) and a missense mutation (c.2542G&amp;gt;C; p.Gly848Arg). The latter are associated with the development of multiple plexiform neurofibromas along spinal nerve roots. We demonstrate that the human nonsense NF1Arg681* and missense NF1Gly848Arg mutations have different effects in the mouse on neurofibromin expression and each recapitulates unique aspects of the NF1 phenotype, depending upon the genetic context when assessed in the homozygous state or when paired with a conditional knockout allele. Whereas the missense Nf1Gly848Arg mutation fails to produce an overt phenotype in the mouse, animals homozygous for the nonsense Nf1Arg681* mutation are not viable. Mice with one Nf1Arg681*allele in combination with a conditional floxed Nf1 allele and the DhhCre transgene (Nf14F\/Arg681*; DhhCre) display disorganized nonmyelinating axons and neurofibromas along the spinal column, which leads to compression of the spinal cord and paralysis. This model will be valuable for novel preclinical testing of nonsense suppression therapies using drugs to target in-frame point mutations that create premature termination codons in patients with NF1.<\/jats:p>","DOI":"10.1242\/dmm.025783","type":"journal-article","created":{"date-parts":[[2016,6,3]],"date-time":"2016-06-03T01:53:41Z","timestamp":1464918821000},"source":"Crossref","is-referenced-by-count":12,"title":["Mice with missense and nonsense <i>NF1<\/i> mutations display divergent phenotypes compared to NF1 patients"],"prefix":"10.1242","author":[{"given":"Kairong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley N.","family":"Turner","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie N.","family":"Brosius","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"},{"name":"Medical Scientist Training Program, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trenton R.","family":"Schoeb","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludwine M.","family":"Messiaen","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Bedwell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt R.","family":"Zinn","sequence":"additional","affiliation":[{"name":"Department of Radiology, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corina","family":"Anastasaki","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Gutmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine, St. Louis MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R.","family":"Korf","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1331-0780","authenticated-orcid":false,"given":"Robert A.","family":"Kesterson","sequence":"additional","affiliation":[{"name":"Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042501242597500_DMM025783C1","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1093\/hmg\/ddg100","article-title":"Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients","volume":"12","author":"Aartsma-Rus","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2021042501242597500_DMM025783C2","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/1479-7364-6-12","article-title":"Genotype-phenotype associations in neurofibromatosis type 1 (NF1): an increased risk of tumor complications in patients with NF1 splice-site mutations?","volume":"6","author":"Alkindy","year":"2012","journal-title":"Hum. Genomics"},{"key":"2021042501242597500_DMM025783C3","doi-asserted-by":"publisher","first-page":"3518","DOI":"10.1093\/hmg\/ddv103","article-title":"Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning","volume":"24","author":"Anastasaki","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"2021042501242597500_DMM025783C4","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1172\/JCI7866","article-title":"Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice","volume":"104","author":"Barton-Davis","year":"1999","journal-title":"J. Clin. Invest."},{"key":"2021042501242597500_DMM025783C5","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1093\/hmg\/2.6.645","article-title":"Mouse neurofibromatosis type 1 cDNA sequence reveals high degree of conservation of both coding and non-coding mRNA segments","volume":"2","author":"Bernards","year":"1993","journal-title":"Hum. Mol. Genet."},{"key":"2021042501242597500_DMM025783C6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaad.2008.12.051","article-title":"Neurofibromatosis type 1","volume":"61","author":"Boyd","year":"2009","journal-title":"J. Am. Acad. Dermatol."},{"key":"2021042501242597500_DMM025783C7","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1101\/gad.8.9.1019","article-title":"Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues","volume":"8","author":"Brannan","year":"1994","journal-title":"Genes Dev."},{"key":"2021042501242597500_DMM025783C8","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.nbd.2008.07.009","article-title":"Gentamicin treatment in exercised mdx mice: identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle","volume":"32","author":"De Luca","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"2021042501242597500_DMM025783C9","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1007\/s00109-002-0363-1","article-title":"Aminoglycoside suppression of a premature stop mutation in a Cftr-\/- mouse carrying a human CFTR-G542X transgene","volume":"80","author":"Du","year":"2002","journal-title":"J. Mol. Med."},{"key":"2021042501242597500_DMM025783C10","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1007\/s00109-006-0045-5","article-title":"Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model","volume":"84","author":"Du","year":"2006","journal-title":"J. Mol. Med."},{"key":"2021042501242597500_DMM025783C11","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1002\/ajmg.a.33139","article-title":"Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service","volume":"152A","author":"Evans","year":"2010","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042501242597500_DMM025783C12","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1136\/jmg.2006.045906","article-title":"Guidelines for the diagnosis and management of individuals with neurofibromatosis 1","volume":"44","author":"Ferner","year":"2007","journal-title":"J. Med. Genet."},{"key":"2021042501242597500_DMM025783C13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/(SICI)1096-8628(19990326)89:1&lt;1::AID-AJMG3&gt;3.0.CO;2-8","article-title":"Epidemiology of neurofibromatosis type 1","volume":"89","author":"Friedman","year":"1999","journal-title":"Am. J. Med. Genet."},{"key":"2021042501242597500_DMM025783C14","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1002\/humu.21387","article-title":"Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: importance of copy neutral LOH","volume":"32","author":"Garcia-Linares","year":"2011","journal-title":"Hum. Mutat."},{"key":"2021042501242597500_DMM025783C15","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.exer.2008.05.016","article-title":"Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa","volume":"87","author":"Guerin","year":"2008","journal-title":"Exp. Eye Res."},{"key":"2021042501242597500_DMM025783C16","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.ymgme.2013.12.007","article-title":"Long-term nonsense suppression therapy moderates MPS I-H disease progression","volume":"111","author":"Gunn","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"2021042501242597500_DMM025783C17","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1002\/humu.22931","article-title":"Correction of a cystic fibrosis splicing mutation by antisense oligonucleotides","volume":"37","author":"Igreja","year":"2016","journal-title":"Hum. Mutat."},{"key":"2021042501242597500_DMM025783C18","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/ng0794-353","article-title":"Tumour predisposition in mice heterozygous for a targeted mutation in Nf1","volume":"7","author":"Jacks","year":"1994","journal-title":"Nat. Genet."},{"key":"2021042501242597500_DMM025783C19","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1172\/JCI60578","article-title":"MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors","volume":"123","author":"Jessen","year":"2013","journal-title":"J. Clin. Invest."},{"key":"2021042501242597500_DMM025783C20","doi-asserted-by":"publisher","first-page":"e60478","DOI":"10.1371\/journal.pone.0060478","article-title":"Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression","volume":"8","author":"Keeling","year":"2013","journal-title":"PLoS ONE"},{"key":"2021042501242597500_DMM025783C21","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1161\/01.ATV.0000118683.99628.42","article-title":"Absence of dystrophin in mice reduces NO-dependent vascular function and vascular density: total recovery after a treatment with the aminoglycoside gentamicin","volume":"24","author":"Loufrani","year":"2004","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021042501242597500_DMM025783C22","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1073\/pnas.0406700102","article-title":"Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles","volume":"102","author":"Lu","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501242597500_DMM025783C23","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1073\/pnas.011408598","article-title":"Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse","volume":"98","author":"Mann","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501242597500_DMM025783C24","first-page":"63","article-title":"NF1 mutational spectrum","volume-title":"Monographs in Human Genetics: Neurofibromatoses","author":"Messiaen","year":"2008"},{"key":"2021042501242597500_DMM025783C25","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1136\/jmedgenet-2012-100978","article-title":"Neurofibromatosis type 1: from genotype to phenotype","volume":"49","author":"Pasmant","year":"2012","journal-title":"J. Med. Genet."},{"key":"2021042501242597500_DMM025783C26","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1016\/S1470-2045(12)70414-X","article-title":"Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial","volume":"13","author":"Robertson","year":"2012","journal-title":"Lancet Oncol."},{"key":"2021042501242597500_DMM025783C27","doi-asserted-by":"publisher","first-page":"2768","DOI":"10.1093\/hmg\/ddp212","article-title":"Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1","volume":"18","author":"Sabbagh","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"2021042501242597500_DMM025783C28","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1093\/hmg\/ddh105","article-title":"Aminoglycoside-mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo","volume":"13","author":"Sangkuhl","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2021042501242597500_DMM025783C29","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1038\/jid.2008.274","article-title":"Mechanisms of loss of heterozygosity in neurofibromatosis type 1-associated plexiform neurofibromas","volume":"129","author":"Steinmann","year":"2009","journal-title":"J. Invest. Dermatol."},{"key":"2021042501242597500_DMM025783C30","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw039","article-title":"NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis-1","author":"Toonen","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2021042501242597500_DMM025783C31","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1093\/hmg\/10.15.1547","article-title":"Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells","volume":"10","author":"van Deutekom","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"2021042501242597500_DMM025783C32","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.ymgme.2011.10.005","article-title":"The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse","volume":"105","author":"Wang","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"2021042501242597500_DMM025783C33","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.ccr.2007.12.027","article-title":"Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells","volume":"13","author":"Wu","year":"2008","journal-title":"Cancer Cell"},{"key":"2021042501242597500_DMM025783C34","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1165\/rcmb.2013-0282OC","article-title":"Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor","volume":"50","author":"Xue","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2021042501242597500_DMM025783C35","doi-asserted-by":"publisher","first-page":"15394","DOI":"10.1073\/pnas.0610878104","article-title":"A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin","volume":"104","author":"Yang","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501242597500_DMM025783C36","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.cell.2008.08.041","article-title":"Nf1-dependent tumors require a microenvironment containing Nf1+\/\u2212- and c-kit-dependent bone marrow","volume":"135","author":"Yang","year":"2008","journal-title":"Cell"},{"key":"2021042501242597500_DMM025783C37","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.jcf.2013.11.009","article-title":"Marked repression of CFTR mRNA in the transgenic Cftr(tm1kth) mouse model","volume":"13","author":"Zhang","year":"2014","journal-title":"J. Cyst. Fibrosis"},{"key":"2021042501242597500_DMM025783C38","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1126\/science.1068452","article-title":"Neurofibromas in NF1: Schwann cell origin and role of tumor environment","volume":"296","author":"Zhu","year":"2002","journal-title":"Science"},{"key":"2021042501242597500_DMM025783C39","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1136\/gut.2008.169805","article-title":"Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons","volume":"59","author":"Zilberberg","year":"2010","journal-title":"Gut"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dmm.025783","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/9\/7\/759\/1870179\/dmm025783.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.025783\/2069390\/dmm_025783v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.025783\/2069390\/dmm_025783v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T22:00:47Z","timestamp":1621375247000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.025783\/257127\/Mice-with-missense-and-nonsense-NF1-mutations"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,1]]},"references-count":39,"URL":"https:\/\/doi.org\/10.1242\/dmm.025783","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2016,1,1]]},"article-number":"dmm.025783"}}