Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome

Christopher A. Wassif, Pinjun Zhu, Lisa Kratz, Patrycja A. Krakowiak, Kevin P. Battaile, Forrest F. Weight, Alexander Grinberg, Robert D. Steiner, Ngozi A. Nwokoro, Richard I. Kelley, Randall R. Stewart, Forbes D. Porter

Research output: Contribution to journalArticle

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 3β-hydroxysterol Δ7-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 3β-hydroxysterol Δ7-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 γ-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.

Original languageEnglish (US)
Pages (from-to)555-564
Number of pages10
JournalHuman Molecular Genetics
Volume10
Issue number6
StatePublished - Mar 15 2001

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Smith-Lemli-Opitz Syndrome
Genetic Models
Intellectual Disability
Oxidoreductases
Cholesterol
Neurons
Muscle Hypotonia
Butyric Acid
Cleft Palate
Frontal Lobe
Serum
Genes
Neurotransmitter Agents
Glutamic Acid
Phenotype
Mutation
Growth

ASJC Scopus subject areas

  • Genetics

Cite this

Wassif, C. A., Zhu, P., Kratz, L., Krakowiak, P. A., Battaile, K. P., Weight, F. F., ... Porter, F. D. (2001). Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome. Human Molecular Genetics, 10(6), 555-564.

Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome. / Wassif, Christopher A.; Zhu, Pinjun; Kratz, Lisa; Krakowiak, Patrycja A.; Battaile, Kevin P.; Weight, Forrest F.; Grinberg, Alexander; Steiner, Robert D.; Nwokoro, Ngozi A.; Kelley, Richard I.; Stewart, Randall R.; Porter, Forbes D.

In: Human Molecular Genetics, Vol. 10, No. 6, 15.03.2001, p. 555-564.

Research output: Contribution to journalArticle

Wassif, CA, Zhu, P, Kratz, L, Krakowiak, PA, Battaile, KP, Weight, FF, Grinberg, A, Steiner, RD, Nwokoro, NA, Kelley, RI, Stewart, RR & Porter, FD 2001, 'Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome', Human Molecular Genetics, vol. 10, no. 6, pp. 555-564.
Wassif, Christopher A. ; Zhu, Pinjun ; Kratz, Lisa ; Krakowiak, Patrycja A. ; Battaile, Kevin P. ; Weight, Forrest F. ; Grinberg, Alexander ; Steiner, Robert D. ; Nwokoro, Ngozi A. ; Kelley, Richard I. ; Stewart, Randall R. ; Porter, Forbes D. / Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome. In: Human Molecular Genetics. 2001 ; Vol. 10, No. 6. pp. 555-564.
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