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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)125-130
Number of pages6
JournalAmerican Journal of Human Genetics
Volume103
Issue number1
DOIs
StatePublished - Jul 5 2018
Externally publishedYes

Keywords

  • cholesterol biosynthesis
  • dysmorphism
  • FDFT1
  • syndactyly

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis'. Together they form a unique fingerprint.

Cite this