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

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is a human autosomal recessiv e syndrome characterized by multiple malformations, a distinct behavioral p henotype with autistic features and mental retardation. RSH/SLOS is due to an inborn error of cholesterol biosynthesis caused by mutation of the 3 bet a -hydroxysterol Delta (7)-reductase gene, To further our understanding of the developmental and neurological processes that underlie the pathophysiol ogy of this disorder, we have developed a mouse model of RSH/SLOS by disrup tion of the BP-hydroxysterol Delta (7)\reductase gene. Here we provide the biochemical, phenotypic and neurophysiological characterization of this gen etic mouse model. As in human patients, the RSH/SLOS mouse has a marked red uction of serum and tissue cholesterol levels and a marked increase of seru m and tissue 7-dehydrocholesterol levels. Phenotypic similarities between t his mouse model and the human syndrome include intra-uterine growth retarda tion, variable craniofacial anomalies including cleft palate, poor feeding with an uncoordinated suck, hypotonia and decreased movement. Neurophysiolo gical studies showed that although the response of frontal cortex neurons t o the neurotransmitter gamma -amino-eta -butyric acid was normal, the respo nse of these same neurons to glutamate was significantly impaired. This fin ding provides insight into potential mechanisms underlying the neurological dysfunction seen in this human mental retardation syndrome and suggests th at this mouse model will allow the testing of potential therapeutic interve ntions.