Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis
Open accessAbstract
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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- Authors
- Coman, D., Vissers, L. E. L. M., Riley, L. G., Kwint, M. P., Hauck, R., Koster, J., Geuer, S., Hopkins, S., Hallinan, B., Sweetman, L., Engelke, U. F. H., Burrow, T. A., Cardinal, J., McGill, J., Inwood, A., Gurnsey, C., Waterham, H. R., Christodoulou, J., Wevers, R. A., & Pitt, J.
- Affiliations
- Griffith University (AU)
- Radboud University Nijmegen (NL)
- The University of Sydney (AU)
- Amsterdam UMC Location University of Amsterdam (NL)
- Children's Hospital of Philadelphia (US)
- Cincinnati Children's Hospital Medical Center (US)
- Baylor University Medical Center (US)
- Radboud University Medical Center (NL)
- University of Arkansas for Medical Sciences (US)
- Wesley Hospital (AU)
- The University of Queensland (AU)
- Children's Health Queensland Hospital and Health Service (AU)
- Royal Brisbane and Women's Hospital (AU)
- The University of Melbourne (AU)
- Corresponding author
- Coman, David
- Pitt, James
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 103
- Issue
- 1
- Pages
- 125-130
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC6037199
- OpenAlex
- W2808114064
- Cited by
- 42
- References
- 13
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 8 · 2019: 3
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Griffith Research Online (submittedVersion)
- Funders
- State Government of Victoria
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- FDFT1, cholesterol biosynthesis, Smith-Lemli-Opitz syndrome, developmental delay, brain abnormalities, syndactyly, facial dysmorphism, aberrant splicing, recessive mutations, monogenic disorders
- MeSH terms
- Exome Sequencing, Child, Child, Preschool, Cholesterol, Enhancer Elements, Genetic, Female, Humans, Infant, Male, Musculoskeletal Abnormalities, Promoter Regions, Genetic, RNA Splicing, Farnesyl-Diphosphate Farnesyltransferase, Smith-Lemli-Opitz Syndrome
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