%0 Journal Article
%T Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis
%A Anita Inwood
%A Barbra Hallinan
%A Christine Gurnsey
%A David Coman
%A Hans R. Waterham
%A James McGill
%A Janet Koster
%A John Cardinal
%A John Christodoulou
%A Larry Sweetman
%A Lisa G. Riley
%A Lisenka E.L.M. Vissers
%A Michael P. Kwint
%A Ron A. Wevers
%A Roxanna Hauck
%A Sarah Hopkins
%A Sinje Geuer
%A T. Andrew Burrow
%A Udo F.H. Engelke
%J Archive of "American Journal of Human Genetics".
%D 2018
%R 10.1016/j.ajhg.2018.05.004
%X 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
%K FDFT1
%K cholesterol biosynthesis
%K syndactyly
%K dysmorphism
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037199/