1. Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis
- Author
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Sinje Geuer, Udo F. H. Engelke, John Cardinal, James McGill, James Pitt, Hans R. Waterham, Janet Koster, John Christodoulou, Anita Inwood, David Coman, Barbra Hallinan, Lisenka E.L.M. Vissers, Sarah Hopkins, Larry Sweetman, Roxanna Hauck, T. Andrew Burrow, Lisa G. Riley, Christine Gurnsey, Ron A. Wevers, Michael Kwint, Laboratory Genetic Metabolic Diseases, and AGEM - Inborn errors of metabolism
- Subjects
Male ,0301 basic medicine ,RNA Splicing ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Squalene ,All institutes and research themes of the Radboud University Medical Center ,Report ,Exome Sequencing ,Genetics ,medicine ,Humans ,Child ,Promoter Regions, Genetic ,Enhancer ,Genetics (clinical) ,Exome sequencing ,Farnesyl-diphosphate farnesyltransferase ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,ATP synthase ,Cholesterol ,Infant ,Zaragozic acid ,medicine.disease ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Musculoskeletal Abnormalities ,Smith-Lemli-Opitz Syndrome ,Enhancer Elements, Genetic ,Farnesyl-Diphosphate Farnesyltransferase ,030104 developmental biology ,chemistry ,Biochemistry ,Smith–Lemli–Opitz syndrome ,Child, Preschool ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) - 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.
- Published
- 2018