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

Autor:	Coman D; 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., Vissers LELM; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands., Riley LG; 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., Kwint MP; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands., Hauck R; Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia., Koster J; Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 105 AZ Amsterdam, the Netherlands., Geuer S; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands., Hopkins S; Division of Neurology, Children's Hospital, Philadelphia, PA 19104, USA., Hallinan B; Division of Neurology, Cincinnati Children's Medical Centre, Cincinnati, OH 45229, USA., Sweetman L; Institute of Metabolic Disease, Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Engelke UFH; Translational Metabolic Laboratory - 830 TML, Department of Laboratory Medicine, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands., Burrow TA; University of Arkansas for Medical Sciences College of Medicine, Department of Pediatrics Little Rock, Arkansas, AR 72205, USA., Cardinal J; Department of Paediatrics, Wesley Hospital, Brisbane, QLD 4066, Australia., McGill J; 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., Inwood A; Department of Metabolic Medicine, Lady Cilento Children's Hospital, Brisbane, QLD 4101, Australia., Gurnsey C; Department of Chemical Pathology, Pathology Queensland, Royal Brisbane & Women's Hospital, Brisbane, QLD 4006, Australia., Waterham HR; Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 105 AZ Amsterdam, the Netherlands., Christodoulou J; 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., Wevers RA; Translational Metabolic Laboratory - 830 TML, Department of Laboratory Medicine, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands., Pitt J; 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.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2018 Jul 05; Vol. 103 (1), pp. 125-130. Date of Electronic Publication: 2018 Jun 14.
DOI:	10.1016/j.ajhg.2018.05.004
Abstrakt:	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. (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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