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Genetic defects in postsqualene cholesterol biosynthesis
F F Moebius1, B U Fitzky, H Glossmann
1Institute of Biochemical Pharmacology, Peter-Mayr-Str. 1, A-6020 Innsbruck, Austria.
Abstract:
In humans and mice, four different genetic defects in the nine biosynthetic steps from lanosterol to cholesterol have been identified. They impair the activity of a putative C3-sterol dehydrogenase (Nshdl, X-linked dominant bare patches/striated mutation in mice), the sterol delta 8-delta 7 isomerase/EBP (Ebp, X-linked dominant tattered mutation in mice; chondrodysplasia punctata (CDPX2) in humans), the delta 24-sterol reductase (autosomal recessive desmosterolosis) and the delta 7-sterol reductase (DHCR7 gene, autosomal recessive Smith-Lemli-Opitz syndrome in humans). These inborn errors in postsqualene cholesterol metabolism result in dysmorphogenetic syndromes of variable severity. The X-linked dominant mutations result in mosaicism in females, as a result of X-inactivation, and midgestational lethality in males. The mechanisms by which the depletion of cholesterol or the accumulation of intermediates impair morphogenetic programs are unclear. So far, no cellular processes that require an intact cholesterol biosynthetic pathway have been identified, although the morphogenetic hedgehog-patched signaling cascade is a candidate.
Insights
Genetic defects in cholesterol synthesis cause developmental disorders. These inborn errors impact sterol metabolism, leading to syndromes of varying severity in humans and mice.
Area of Science:
- Biochemistry
- Genetics
- Developmental Biology
Background:
- Four genetic defects in cholesterol biosynthesis from lanosterol have been identified in humans and mice.
- These defects affect enzymes including C3-sterol dehydrogenase, sterol isomerase, delta 24-sterol reductase, and delta 7-sterol reductase.
- Inborn errors in postsqualene cholesterol metabolism lead to dysmorphogenetic syndromes.
Purpose of the Study:
- To investigate the genetic defects in cholesterol biosynthesis and their resulting dysmorphogenetic syndromes.
- To understand the mechanisms underlying the impact of cholesterol depletion or intermediate accumulation on morphogenetic programs.
Main Methods:
- Identification of genetic defects in specific enzymes of the cholesterol biosynthetic pathway.
- Analysis of phenotypic consequences in humans and mice, including mosaicism and lethality.
- Investigation of potential cellular processes affected by cholesterol metabolism, such as hedgehog-patched signaling.
Main Results:
- Identified four genetic defects affecting key enzymes in cholesterol synthesis.
- Observed variable severity of dysmorphogenetic syndromes associated with these defects.
- Noted X-linked dominant mutations cause mosaicism in females and midgestational lethality in males.
Conclusions:
- Genetic defects in cholesterol biosynthesis result in significant developmental abnormalities.
- The precise mechanisms by which cholesterol metabolism impacts development remain unclear.
- The hedgehog-patched signaling cascade is a potential candidate pathway affected by these metabolic disruptions.