학술논문
A Mouse Model with a Frameshift Mutation in the Nuclear Factor I/X (NFIX) Gene Has Phenotypic Features of Marshall‐Smith Syndrome
Document Type
article
Author
Kreepa G. Kooblall; Mark Stevenson; Michelle Stewart; Lachlan Harris; Oressia Zalucki; Hannah Dewhurst; Natalie Butterfield; Houfu Leng; Tertius A. Hough; Da Ma; Bernard Siow; Paul Potter; Roger D. Cox; Stephen D.M. Brown; Nicole Horwood; Benjamin Wright; Helen Lockstone; David Buck; Tonia L. Vincent; Fadil M. Hannan; J.H. Duncan Bassett; Graham R. Williams; Kate E. Lines; Michael Piper; Sara Wells; Lydia Teboul; Raoul C. Hennekam; Rajesh V. Thakker
Source
JBMR Plus, Vol 7, Iss 6, Pp n/a-n/a (2023)
Subject
Language
English
ISSN
2473-4039
Abstract
The nuclear factor I/X (NFIX) 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). NFIX mutations associated with MAL mainly cluster in exon 2 and are cleared by nonsense‐mediated decay (NMD) leading to NFIX haploinsufficiency, whereas NFIX 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 NFIX mutations have distinct consequences on NFIX expression. To elucidate the in vivo effects of MSS‐associated NFIX exon 7 mutations, we used CRISPR‐Cas9 to generate mouse models with exon 7 deletions that comprised: a frameshift deletion of two nucleotides (Nfix Del2); in‐frame deletion of 24 nucleotides (Nfix Del24); and deletion of 140 nucleotides (Nfix Del140). Nfix+/Del2, Nfix+/Del24, Nfix+/Del140, NfixDel24/Del24, and NfixDel140/Del140 mice were viable, normal, and fertile, with no skeletal abnormalities, but NfixDel2/Del2 mice had significantly reduced viability (p