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Generation and validation of a conditional knockout mouse model for the study of the Smith-Lemli-Opitz syndrome

Generation and validation of a conditional knockout mouse model for the study of the Smith-Lemli-Opitz syndrome

Authors :
Babunageswararao Kanuri
Vincent Fong
Sithara Raju Ponny
Keri A. Tallman
Sriganesh Ramachandra Rao
Ned Porter
Steven J. Fliesler
Shailendra B. Patel
Source :
Journal of Lipid Research, Vol 62, Iss , Pp 100002- (2021)
Publication Year :
2021
Publisher :
Elsevier, 2021.

Abstract

Smith-Lemli-Opitz Syndrome (SLOS) is a developmental disorder (OMIM #270400) caused by autosomal recessive mutations in the Dhcr7 gene, which encodes the enzyme 3β-hydroxysterol-Δ7 reductase. SLOS patients present clinically with dysmorphology and neurological, behavioral, and cognitive defects, with characteristically elevated levels of 7-dehydrocholesterol (7-DHC) in all bodily tissues and fluids. Previous mouse models of SLOS have been hampered by postnatal lethality when Dhcr7 is knocked out globally, while a hypomorphic mouse model showed improvement in the biochemical phenotype with aging and did not manifest most other characteristic features of SLOS. We report the generation of a conditional knockout of Dhcr7 (Dhcr7flx/flx), validated by generating a mouse with a liver-specific deletion (Dhcr7L-KO). Phenotypic characterization of liver-specific knockout mice revealed no significant changes in viability, fertility, growth curves, liver architecture, hepatic triglyceride secretion, or parameters of systemic glucose homeostasis. Furthermore, qPCR and RNA-Seq analyses of livers revealed no perturbations in pathways responsible for cholesterol synthesis, either in male or in female Dhcr7L-KO mice, suggesting that hepatic disruption of postsqualene cholesterol synthesis leads to minimal impact on sterol metabolism in the liver. This validated conditional Dhcr7 knockout model may now allow us to systematically explore the pathophysiology of SLOS, by allowing for temporal, cell and tissue-specific loss of DHCR7.

Details

Language :
English
ISSN :
00222275
Volume :
62
Issue :
100002-
Database :
Directory of Open Access Journals
Journal :
Journal of Lipid Research
Publication Type :
Academic Journal
Accession number :
edsdoj.fffd503a6747449ba298d727bfc30580
Document Type :
article
Full Text :
https://doi.org/10.1194/jlr.RA120001101