Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis

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Coman, David
Vissers, Lisenka ELM
Riley, Lisa G
Kwint, Michael P
Hauck, Roxanna
Koster, Janet
Geuer, Sinje
Hopkins, Sarah
Hallinan, Barbra
Sweetman, Larry
Engelke, Udo FH
Burrow, T Andrew
Cardinal, John
McGill, James
Inwood, Anita
Gurnsey, Christine
Waterham, Hans R
Christodoulou, John
Wevers, Ron A
Pitt, James
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2018
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Abstract

Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.

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American Journal of Human Genetics
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103
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1
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Biological sciences
Biomedical and clinical sciences
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