{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:26:42Z","timestamp":1790692002390,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JBMR Plus"],"published-print":{"date-parts":[[2023,6]]},"abstract":"\n The nuclear factor I\/X (\n NFIX<\/jats:italic>\n ) gene encodes a ubiquitously expressed transcription factor whose mutations lead to two allelic disorders characterized by developmental, skeletal, and neural abnormalities, namely, Malan syndrome (MAL) and Marshall\u2013Smith syndrome (MSS).\n NFIX<\/jats:italic>\n mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense\u2010mediated decay (NMD) leading to NFIX haploinsufficiency, whereas\n NFIX<\/jats:italic>\n mutations associated with MSS are clustered in exons 6\u201310 and escape NMD and result in the production of dominant\u2010negative mutant NFIX proteins. Thus, different\n NFIX<\/jats:italic>\n mutations have distinct consequences on\n NFIX<\/jats:italic>\n expression. To elucidate the\n in vivo<\/jats:italic>\n effects of MSS\u2010associated\n NFIX<\/jats:italic>\n exon 7 mutations, we used CRISPR\u2010Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (\n Nfix<\/jats:italic>\n Del2); in\u2010frame deletion of 24 nucleotides (\n Nfix<\/jats:italic>\n Del24); and deletion of 140 nucleotides (\n Nfix<\/jats:italic>\n Del140).\n Nfix<\/jats:italic>\n \n +\/Del2<\/jats:italic>\n <\/jats:sup>\n ,\n Nfix<\/jats:italic>\n \n +\/Del24<\/jats:italic>\n <\/jats:sup>\n ,\n Nfix<\/jats:italic>\n \n +\/Del140<\/jats:italic>\n <\/jats:sup>\n ,\n Nfix<\/jats:italic>\n \n Del24\/Del24<\/jats:italic>\n <\/jats:sup>\n , and\n Nfix<\/jats:italic>\n \n Del140\/Del140<\/jats:italic>\n <\/jats:sup>\n mice were viable, normal, and fertile, with no skeletal abnormalities, but\n Nfix<\/jats:italic>\n \n Del2\/Del2<\/jats:italic>\n <\/jats:sup>\n mice had significantly reduced viability (\n p<\/jats:italic>\n \u2009<\u20090.002) and died at 2\u20133\u2009weeks of age.\n Nfix<\/jats:italic>\n Del2 was not cleared by NMD, and\n \n Nfix\n Del2\/Del2<\/jats:sup>\n <\/jats:italic>\n mice, when compared to\n Nfix<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n and\n Nfix<\/jats:italic>\n \n +\/Del2<\/jats:italic>\n <\/jats:sup>\n mice, had: growth retardation; short stature with kyphosis; reduced skull length; marked porosity of the vertebrae with decreased vertebral and femoral bone mineral content; and reduced caudal vertebrae height and femur length. Plasma biochemistry analysis revealed\n Nfix<\/jats:italic>\n \n Del2\/Del2<\/jats:italic>\n <\/jats:sup>\n mice to have increased total alkaline phosphatase activity but decreased C\u2010terminal telopeptide and procollagen\u2010type\u20101\u2010N\u2010terminal propeptide concentrations compared to\n Nfix<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n and\n Nfix<\/jats:italic>\n \n +\/Del2<\/jats:italic>\n <\/jats:sup>\n mice.\n Nfix<\/jats:italic>\n \n Del2\/Del2<\/jats:italic>\n <\/jats:sup>\n mice were also found to have enlarged cerebral cortices and ventricular areas but smaller dentate gyrus compared to\n Nfix<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n mice. Thus,\n Nfix<\/jats:italic>\n \n Del2\/Del2<\/jats:italic>\n <\/jats:sup>\n mice provide a model for studying the\n in vivo<\/jats:italic>\n effects of NFIX mutants that escape NMD and result in developmental abnormalities of the skeletal and neural tissues that are associated with MSS. \u00a9 2023 The Authors.\n JBMR Plus<\/jats:italic>\n published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n <\/jats:p>","DOI":"10.1002\/jbm4.10739","type":"journal-article","created":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T22:34:30Z","timestamp":1678833270000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Mouse Model with a Frameshift Mutation in the Nuclear Factor I\/X (\n \n NFIX<\/i>\n <\/scp>\n ) Gene Has Phenotypic Features of\n Marshall\u2010Smith<\/scp>\n Syndrome"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9547-2067","authenticated-orcid":false,"given":"Kreepa G.","family":"Kooblall","sequence":"first","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Stewart","sequence":"additional","affiliation":[{"name":"MRC Harwell, Mary Lyon Centre Harwell Science and Innovation Campus Oxfordshire 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