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

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...

Full description

Saved in:
Bibliographic Details
Published in:American journal of human genetics 2018-07, Vol.103 (1), p.125-130
Main Authors: Coman, David, Vissers, Lisenka E.L.M., Riley, Lisa G., Kwint, Michael P., Hauck, Roxanna, Koster, Janet, Geuer, Sinje, Hopkins, Sarah, Hallinan, Barbra, Sweetman, Larry, Engelke, Udo F.H., Burrow, T. Andrew, Cardinal, John, McGill, James, Inwood, Anita, Gurnsey, Christine, Waterham, Hans R., Christodoulou, John, Wevers, Ron A., Pitt, James
Format: Article
Language:English
Subjects:
Child
Child, Preschool
Cholesterol - genetics
cholesterol biosynthesis
dysmorphism
Enhancer Elements, Genetic - genetics
Farnesyl-Diphosphate Farnesyltransferase - genetics
FDFT1
Female
Humans
Infant
Male
Musculoskeletal Abnormalities - genetics
Promoter Regions, Genetic - genetics
RNA Splicing - genetics
Smith-Lemli-Opitz Syndrome - genetics
syndactyly
Whole Exome Sequencing - methods
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2018.05.004