Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith--Lemli--Opitz syndrome
Abstract
The RSH/Smith--Lemli--Opitz syndrome (RSH/SLOS) is a human autosomal recessive syndrome characterized by multiple malformations, a distinct behavioral phenotype with autistic features and mental retardation. RSH/SLOS is due to an inborn error of cholesterol biosynthesis caused by mutation of the 3 beta-hydroxysterol Delta(7)-reductase gene. To further our understanding of the developmental and neurological processes that underlie the pathophysiology of this disorder, we have developed a mouse model of RSH/SLOS by disruption of the 3 beta-hydroxysterol Delta(7)-reductase gene. Here we provide the biochemical, phenotypic and neurophysiological characterization of this genetic mouse model. As in human patients, the RSH/SLOS mouse has a marked reduction of serum and tissue cholesterol levels and a marked increase of serum and tissue 7-dehydrocholesterol levels. Phenotypic similarities between this mouse model and the human syndrome include intra-uterine growth retardation, variable craniofacial anomalies including cleft palate, poor feeding with an uncoordinated suck, hypotonia and decreased movement. Neurophysiological studies showed that although the response of frontal cortex neurons to the neurotransmitter gamma-amino-n-butyric acid was normal, the response of these same neurons to glutamate was significantly impaired. This finding provides insight into potential mechanisms underlying the neurological dysfunction seen in this human mental retardation syndrome and suggests that this mouse model will allow the testing of potential therapeutic interventions.
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Dhcr7Δ3-5/T93M mice are heterozygous for a Dhcr7 targeting vector containing a neomycin insertion that deletes Dhcr7 exons III, IV and part of V, and carry a dinucleotide mutation in codon 89.
“are heterozygous for a Dhcr7 targeting vector containing a neomycin insertion, which results in deletion of Dhcr7 exons III, IV and part of V, along with a dinucleotide mutation in codon 89 (Correa-Cerro et al., 2006; Wassif et al., 2001).”
From Sterol dysregulation in Smith–Lemli–Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk (2022) · cites this paper as Wassif et al., 2001
The “Disruption of the Dhcr7 gene” section describes a targeting vector that inserts a neomycin gene and deletes exons III, IV and part of V; it also reports heterozygous mice. It does not describe Dhcr7Δ3-5/T93M mice or a dinucleotide mutation at codon 89. Page numbers are not available in our copy. (LLM, conf=0.88)
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- Authors
- Wassif, C. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Wassif, C. A.
- ORCID
- Wassif, C. A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-03-01
- Volume
- 10
- Issue
- 6
- Pages
- 555-564
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2137465274
- Cited by
- 164
- References
- 6
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 6 · 2018: 2 · 2017: 5 · 2016: 11 · 2015: 7 · 2014: 8 · 2013: 2 · 2012: 9
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30hd033703-05)
- National Center for Research Resources (M01RR000334, RR00334-33S3)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (5P30-HD33703-04)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Smith-Lemli-Opitz syndrome, cholesterol biosynthesis, mouse model, 7-dehydrocholesterol, hypotonia, craniofacial anomalies, cleft palate, intellectual disability, autism-like behavior, glutamate response, GABA response, neurophysiology
- MeSH terms
- Animals, Disease Models, Animal, Mice, Inbred C57BL, Oxidoreductases, Phenotype, Smith-Lemli-Opitz Syndrome, Oxidoreductases Acting on CH-CH Group Donors, Mice
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