Reduced cholesterol levels impair Smoothened activation in Smith-Lemli-Opitz Syndrome
Robert Blassberg
James I MacRae
James Briscoe
John Jacob
10779/crick.12601667.v1
https://crick.figshare.com/articles/journal_contribution/Reduced_cholesterol_levels_impair_Smoothened_activation_in_Smith-Lemli-Opitz_Syndrome/12601667
Smith-Lemli-Opitz syndrome (SLOS) is a common autosomal-recessive disorder that results from mutations in the gene encoding the cholesterol biosynthetic enzyme 7-dehydrocholesterol reductase (DHCR7). Impaired DHCR7 function is associated with a spectrum of congenital malformations, intellectual impairment, epileptiform activity and autism spectrum disorder. Biochemically, there is a deficit in cholesterol and an accumulation of its metabolic precursor 7-dehydrocholesterol (7DHC) in developing tissues. Morphological abnormalities in SLOS resemble those seen in congenital Sonic Hedgehog (SHH)-deficient conditions, leading to the proposal that the pathogenesis of SLOS is mediated by aberrant SHH signalling. SHH signalling is transduced through the transmembrane protein Smoothened (SMO), which localizes to the primary cilium of a cell on activation and is both positively and negatively regulated by sterol molecules derived from cholesterol biosynthesis. One proposed mechanism of SLOS involves SMO dysregulation by altered sterol levels, but the salient sterol species has not been identified. Here, we clarify the relationship between disrupted cholesterol metabolism and reduced SHH signalling in SLOS by modelling the disorder in vitro. Our results indicate that a deficit in cholesterol, as opposed to an accumulation of 7DHC, impairs SMO activation and its localization to the primary cilium.
2020-07-15 08:53:13
Animals
Cells, Cultured
Cholesterol
Dehydrocholesterols
Humans
Mice
Mutation
NIH 3T3 Cells
Oxidoreductases
Oxidoreductases Acting on CH-CH Group Donors
Phenotype
Smith-Lemli-Opitz Syndrome
Smoothened Receptor
Briscoe FC001051
MET
Genetics & Heredity
06 Biological Sciences
11 Medical and Health Sciences