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

David Coman; Lisenka E L M Vissers; Lisa G Riley; Michael P Kwint; Roxanna Hauck; Janet Koster; Sinje Geuer; Sarah Hopkins; Barbra Hallinan; Larry Sweetman; Udo F H Engelke; T Andrew Burrow; John Cardinal; James McGill; Anita Inwood; Christine Gurnsey; Hans R Waterham; John Christodoulou; Ron A Wevers; James Pitt

doi:10.1016/j.ajhg.2018.05.004

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

Am J Hum Genet. 2018 Jul 5;103(1):125-130. doi: 10.1016/j.ajhg.2018.05.004. Epub 2018 Jun 14.

Authors

David Coman¹, Lisenka E L M Vissers², Lisa G Riley³, Michael P Kwint², Roxanna Hauck⁴, Janet Koster⁵, Sinje Geuer², Sarah Hopkins⁶, Barbra Hallinan⁷, Larry Sweetman⁸, Udo F H Engelke⁹, T Andrew Burrow¹⁰, John Cardinal¹¹, James McGill¹², Anita Inwood¹³, Christine Gurnsey¹⁴, Hans R Waterham⁵, John Christodoulou¹⁵, Ron A Wevers⁹, James Pitt¹⁶

Affiliations

¹ Department of Metabolic Medicine, Lady Cilento Children's Hospital, Brisbane, QLD 4101, Australia; Department of Paediatrics, Wesley Hospital, Brisbane, QLD 4066, Australia; School of Medicine, University of Queensland, Brisbane, QLD 4067, Australia; School of Medicine, Griffith University, Gold Coast, QLD 4222, Australia. Electronic address: david.coman@health.qld.gov.au.
² Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
³ Genetic Metabolic Disorders Research Group, Sydney Children's Hospital Network, Sydney, NSW 2145, Australia; Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
⁴ Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia.
⁵ Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 105 AZ Amsterdam, the Netherlands.
⁶ Division of Neurology, Children's Hospital, Philadelphia, PA 19104, USA.
⁷ Division of Neurology, Cincinnati Children's Medical Centre, Cincinnati, OH 45229, USA.
⁸ Institute of Metabolic Disease, Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA.
⁹ Translational Metabolic Laboratory - 830 TML, Department of Laboratory Medicine, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
¹⁰ University of Arkansas for Medical Sciences College of Medicine, Department of Pediatrics Little Rock, Arkansas, AR 72205, USA.
¹¹ Department of Paediatrics, Wesley Hospital, Brisbane, QLD 4066, Australia.
¹² Department of Metabolic Medicine, Lady Cilento Children's Hospital, Brisbane, QLD 4101, Australia; Department of Chemical Pathology, Pathology Queensland, Royal Brisbane & Women's Hospital, Brisbane, QLD 4006, Australia; School of Medicine, University of Queensland, Brisbane, QLD 4067, Australia.
¹³ Department of Metabolic Medicine, Lady Cilento Children's Hospital, Brisbane, QLD 4101, Australia.
¹⁴ Department of Chemical Pathology, Pathology Queensland, Royal Brisbane & Women's Hospital, Brisbane, QLD 4006, Australia.
¹⁵ Genetic Metabolic Disorders Research Group, Sydney Children's Hospital Network, Sydney, NSW 2145, Australia; Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute, Melbourne VIC 3052, Australia; Genetic Metabolic Disorders Research Group, Sydney Children's Hospital Network, Sydney NSW 2145, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
¹⁶ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: james.pitt@vcgs.org.au.

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.

Keywords: FDFT1; cholesterol biosynthesis; dysmorphism; syndactyly.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Child
Child, Preschool
Cholesterol / genetics*
Enhancer Elements, Genetic / genetics
Exome Sequencing / methods
Farnesyl-Diphosphate Farnesyltransferase / genetics*
Female
Humans
Infant
Male
Musculoskeletal Abnormalities / genetics*
Promoter Regions, Genetic / genetics
RNA Splicing / genetics
Smith-Lemli-Opitz Syndrome / genetics

Substances

Cholesterol
Farnesyl-Diphosphate Farnesyltransferase