Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis David Coman, Lisenka E.L.M.

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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 The American Journal of Human Genetics Volume 103, Issue 1, Pages 125-130 (July 2018) DOI: 10.1016/j.ajhg.2018.05.004 Copyright © 2018 Terms and Conditions

Figure 1 Schematic Representation of the Isoprenoid/Cholesterol Biosynthesis Pathway Metabolites that accumulate as a result of squalene synthase deficiency are underlined (pathway re-drawn based on Tansey and Shechter13). The American Journal of Human Genetics 2018 103, 125-130DOI: (10.1016/j.ajhg.2018.05.004) Copyright © 2018 Terms and Conditions

Figure 2 Facial Characteristics Individual 1 at 3 years of age (A) and 6 years of age (B) and individual 2 at 5 weeks of age (C) and 3 years of age (D). Dysmorphic features include depressed nasal bridge, low-set posteriorly rotated ears, square nasal tip, epicanthic folds, mild micrognathia, and retrognathia. The American Journal of Human Genetics 2018 103, 125-130DOI: (10.1016/j.ajhg.2018.05.004) Copyright © 2018 Terms and Conditions

Figure 3 Urine Metabolite Profiles (A) Urine organic acid GC-MS profiles of individual 1 (top) and a control subject (bottom). Normal urine components are indicated in italics. Numbered peaks indicate abnormal metabolites: (1) methylsuccinic, (2) mevalonic lactone, (3) mesaconic acid, (4) 2-methylgluatic acid, (5) 3-methyladipic acid, (6) 3-methylhex-3-enedioic acid, (7) 3-methylhex-2-endioic acid, (8) 2,6-dimethylheptanedioic acid, (9) unknown, (10) 3-methylhex-2,4-dienedioic, (11) 2,6-dimethylhept-2-enedioic acid, (12) 3,7-dimethyloctanedioic, and (13) 3,7-dimethyl-2,6-dienedioic. Control values are given in Figure S1. (B) One-dimensional 500 MHz 1H-NMR spectra of urine of individual 1 and age-matched control subject measured at pH 2.5 (regions 5.60–6.50 ppm and 1.50–2.25 ppm). The insert shows the structure of 3-methylhex-2,4-dienedioic acid. Proton assignments of 3-methylhex-3,4-dienedioic acid (A) and other farnesol-derived dicarboxylic acids (asterisk). The American Journal of Human Genetics 2018 103, 125-130DOI: (10.1016/j.ajhg.2018.05.004) Copyright © 2018 Terms and Conditions

Figure 4 Schematic Representation of FDFT1, the Variants Identified in Individuals 1, 2, and 3, and Functional Follow-up (A) The maternal deletion identified in the sibship extends ∼50 kb more proximally, but no other genes are included. Genomic positions are based on hg19. Red horizontal lines indicate deleted sequence. For the paternal mutation in individuals 1 and 2, the wild-type protein amino acid sequence is provided in gray, whereas the predicted sequence of the splice mutation is shown in red. (B) Western blot analysis of individuals 1 (Ind 1) and 2 (Ind 2), using two different culturing conditions (fetal bovine serum [FBS] and lipid depleted [LD-] FBS), using an antibody to detect FDFT1 in fibroblast of individuals 1 and 2. Alpha-tubulin was used as loading control. FDFT1 reduction is more prominent when cells were cultured under lipid depletion. (C) Isoform-specific PCR using cDNA generated from EBV-transformed PBMCs of individual 3 (Ind 3) was used for the detection of FDFT1 isoforms. Three FDFT1 isoforms could not be detected in individual 3 whereas these were present in EBV-transformed PBMCs of a control individual. The addition of cycloheximide (CHX; - absent, + present) did not facilitate expression detection. Profile of all isoforms is presented in Figure S5. (D) The genomic segment containing the homozygous 16 bp deletion in individual 3 was tested for promoter activity using a luciferase assay, which showed significantly reduced activity when compared to the control construct containing the wild-type sequence (two-tailed t test, p = 2.9 × 10−6). ∗∗∗p < 0.001. Error bars represent one SD. The American Journal of Human Genetics 2018 103, 125-130DOI: (10.1016/j.ajhg.2018.05.004) Copyright © 2018 Terms and Conditions