A Mouse Model with a Frameshift Mutation in the Nuclear Factor I/X () Gene Has Phenotypic Features of Marshall-Smith Syndrome.

The nuclear factor I/X () 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-Smith syndrome (MSS). mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense-mediated decay (NMD) leading to NFIX haploinsufficiency, whereas mutations associated with MSS are clustered in exons 6-10 and escape NMD and result in the production of dominant-negative mutant NFIX proteins. Thus, different mutations have distinct consequences on expression. To elucidate the effects of MSS-associated exon 7 mutations, we used CRISPR-Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides ( Del2); in-frame deletion of 24 nucleotides ( Del24); and deletion of 140 nucleotides ( Del140). , , , , and mice were viable, normal, and fertile, with no skeletal abnormalities, but mice had significantly reduced viability ( < 0.002) and died at 2-3 weeks of age. Del2 was not cleared by NMD, and mice, when compared to and 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 mice to have increased total alkaline phosphatase activity but decreased C-terminal telopeptide and procollagen-type-1-N-terminal propeptide concentrations compared to and mice. mice were also found to have enlarged cerebral cortices and ventricular areas but smaller dentate gyrus compared to mice. Thus, mice provide a model for studying the effects of NFIX mutants that escape NMD and result in developmental abnormalities of the skeletal and neural tissues that are associated with MSS. © 2023 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.