Abstract
Mutations in the gene encoding Lamin B receptor (LBR), a nuclear-membrane protein with sterol reductase activity, have been linked to rare human disorders. Phenotypes range from a benign blood disorder, such as Pelger-Huet anomaly (PHA), affecting the morphology and chromatin organization of white blood cells, to embryonic lethality as for Greenberg dysplasia (GRBGD). Existing PHA mouse models do not fully recapitulate the human phenotypes, hindering efforts to understand the molecular etiology of this disorder. Here we show, using CRISPR/Cas-9 gene editing technology, that a 236bp N-terminal deletion in the mouse Lbr gene, generating a protein missing the N-terminal domains of LBR, presents a superior model of human PHA. Further, we address recent reports of a link between Lbr and defects in X chromosome inactivation (XCI) and show that our mouse mutant displays minor X chromosome inactivation defects that do not lead to any overt phenotypes in vivo. We suggest that our N-terminal deletion model provides a valuable pre-clinical tool to the research community and will aid in further understanding the etiology of PHA and the diverse functions of LBR.
Highlights
Mutations in the gene encoding Lamin B receptor (LBR), a nuclear-membrane protein with sterol reductase activity, have been linked to rare human disorders
Our analysis suggests that our N-terminal mutant mouse more closely reproduces the human Pelguer–Huet phenotype than currently available mouse models, which only harbor mutations in the hydrophobic domain of LBR5,9
Our model suggests that the N-terminal of LBR plays a role in heterochromatin organization[28] and random X chromosome inactivation (XCI) in differentiating embryonic stem cells (ESCs) as previously reported[11,24] but is apparently redundant for XCI functions in vivo, similar to what has been seen with Rnf[12], Xist’s major activator[29]
Summary
Mutations in the gene encoding Lamin B receptor (LBR), a nuclear-membrane protein with sterol reductase activity, have been linked to rare human disorders. Considering the discrepancies between the human diseases and mouse model phenotypes, LBR’s diverse and emerging cellular functions, novel mouse models are needed for a better understanding of its roles in development and XCI. For these reasons, we have generated and characterized a novel mouse model, allowing us to separate the activities of LBR N-terminal domains from the sterol reductase domain. We have generated and characterized a novel mouse model, allowing us to separate the activities of LBR N-terminal domains from the sterol reductase domain We report that this model closely recapitulates the phenotypes of the human disease (PHA) and shows minor XCI defects
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