The Smith-Lemli-Opitz syndrome is a mental retardation/malformation syndrome with behavioral components of autism. It is caused by a deficiency in 3β-hydroxysteroid-Δ7-reductase (DHCR7), the enzyme required for the terminal enzymatic step of cholesterol biosynthesis. The availability of Smith-Lemli-Opitz syndrome mouse models has made it possible to investigate the genesis of the malformations associated with this syndrome. Dhcr7 gene modification (Dhcr7–/–) results in neonatal lethality and multiple organ system malformations. Pathology includes cleft palate, pulmonary hypoplasia, cyanosis, impaired cortical response to glutamate, and hypermorphic development of hindbrain serotonergic neurons. For the current study, hindbrain regions microdissected from gestational day 14 Dhcr7–/–, Dhcr7+/– and Dhcr7+/+ fetuses were processed for expression profiling analyses using Affymetrix oligonucleotide arrays and filtered using statistical significance (S-score) of change in gene expression. Of the 12,000 genes analyzed, 91 were upregulated and 98 were downregulated in the Dhcr7–/– hindbrains when compared to wild-type animals. Fewer affected genes, representing a reduced affect on these pathways, were identified in heterozygous animals. Hierarchical clustering identified altered expression of genes associated with cholesterol homeostasis, cell cycle control and apoptosis, neurodifferentiation and embryogenesis, transcription and translation, cellular transport, neurodegeneration, and neuronal cytoskeleton. Of particular interest, Dhcr7 gene modification elicited dynamic changes in genes involved in axonal guidance. In support of the microarray findings, immunohistochemical analyses of the netrin/deleted in colorectal cancer axon guidance pathway illustrated midline commissural deficiencies and hippocampal pathfinding errors in Dhcr7–/– mice. The results of these studies aid in providing insight into the genesis of human cholesterol-related birth defects and neurodevelopmental disorders and highlight specific areas for future investigation.

Keywords:
Smith-Lemli-Opitz Syndrome, Autism, Sonic hedgehog, Netrin, Microarray, Cholesterol biosynthesis
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© 2005 S. Karger AG, Basel
2005
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