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• W2808114064 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. 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. The isoprenoid biosynthesis pathway (Figure 1), essential for numerous biological processes, can be divided into a pre-squalene (also named the mevalonate pathway) and a post-squalene pathway, the latter specifically involved in the synthesis of sterol isoprenoids, including cholesterol. Cholesterol serves as an important structural component of the cell membrane and myelin but is also the precursor of oxysterols, steroid hormones, and bile acids.1Waterham H.R. Defects of cholesterol biosynthesis.FEBS Lett. 2006; 580: 5442-5449Crossref PubMed Scopus (87) Google Scholar The two-step enzymatic conversion of farnesyl-pyrophosphate (FPP) to squalene by squalene synthase is the first committed step in cholesterol biosynthesis.2Schechter I. Conrad D.G. Hart I. Berger R.C. McKenzie T.L. Bleskan J. Patterson D. Localization of the squalene synthase gene (FDFT1) to human chromosome 8p22-p23.1.Genomics. 1994; 20: 116-118Crossref PubMed Scopus (25) Google Scholar, 3Do R. Kiss R.S. Gaudet D. Engert J.C. Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway.Clin. Genet. 2009; 75: 19-29Crossref PubMed Scopus (80) Google Scholar We identified three individuals, a sibship and an unrelated child, whose urine metabolic profiles were suggestive of a cholesterol biosynthesis defect. (For all individuals, informed consent for genetic testing was obtained. For individuals 1 and 2, additional written consent was obtained for photo publication. Ethics approval was provided by Royal Children’s Hospital and Health Service Ethics Committee and Sydney Children’s Hospitals Network Human Research Ethics Committee.) Salient clinical features include facial dysmorphisms (Figure 2), dry skin with photosensitivity, generalized tonic-clonic seizures, structural brain malformations, cortical visual impairment, profound global developmental delay, and genital malformations in the two males (Table 1, see Supplemental Note). The gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy profiles yielded a consistent and complex pattern of abnormal metabolites including the accumulation of methylsuccinic acid, mevalonate lactone, mesaconic acid, and 3-methyladipic acid. Additionally, we observed saturated and unsaturated branched-chain dicarboxylic acids and glucuronides derived from farnesol (Figure 3). A similar metabolite profile has previously been observed in the urine of animal models and humans treated with pharmacological inhibitors of squalene synthase, as well as in animals loaded with farnesol.4Jemal M. Ouyang Z. Gas chromatography-mass spectrometric method for quantitative determination in human urine of dicarboxylic (dioic) acids produced in the body as a consequence of cholesterol biosynthesis inhibition.J. Chromatogr. B Biomed. Sci. Appl. 1998; 709: 233-241Crossref PubMed Scopus (3) Google Scholar, 5Vaidya S. Bostedor R. Kurtz M.M. Bergstrom J.D. Bansal V.S. Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A.Arch. Biochem. Biophys. 1998; 355: 84-92Crossref PubMed Scopus (46) Google Scholar, 6Bostedor R.G. Karkas J.D. Arison B.H. Bansal V.S. Vaidya S. Germershausen J.I. Kurtz M.M. Bergstrom J.D. Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid A or with farnesol.J. Biol. Chem. 1997; 272: 9197-9203Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar To confirm that the abnormal organic acids observed in the affected individuals derive from farnesol, we analyzed urine from a control subject after an oral farnesol load, which resulted in a similar metabolite profile (Figure S1). Plasma cholesterol in the three affected individuals was decreased (2.5–2.8 mmol/L; reference 3.0–5.5), and both HDL and LDL cholesterol levels were decreased or low normal (Table 1). Plasma total farnesol levels (the sum of free farnesol and farnesyl-pyrophosphate) in affected individuals were, however, significantly increased (1.5–3.9 μmol/L; reference < 0.12; Table 1) while plasma squalene levels were reduced or normal (0.17–0.93 μmol/L; reference 0.36–1.04). Thus, the body fluid metabolite profile of the affected individuals was strongly suggestive of a cholesterol biosynthesis defect at the level of squalene synthase, converting farnesyl-pyrophosphate into squalene.Table 1Summary of Key Clinical, Biochemical, and Molecular FeaturesIndividual 1Individual 2Individual 3Age at presentationday 5 with seizuresday 5 with seizuresfirst week of life with seizuresCurrent age10 years old7 years old9 years oldGenderFemaleMaleMaleGestation37/4039/4039/40Birth weight2,600 g (40th percentile)2,750 g (10th percentile)3,033 g (25th percentile)Birth length47 cm (50th percentile)49 cm (30th percentile)50 cm (50th percentile)Birth head circumference32.5 cm (50th percentile)34 cm (50th percentile)33 cm (10th percentile)EthnicityEuropeanEuropeanEuropeanParental relationshipnon-consanguineousnon-consanguineousnon-consanguineousMRI brain abnormalitieshypoplastic corpus callosum, white matter losshypoplastic corpus callosum, white matter lossdiffuse polymicrogyria, central white matter and cortical volume lossSeizuresyes, neonatal onsetyes, neonatal onsetyes, neonatal onsetGlobal developmental delayprofound across all developmental modalitiesprofound across all developmental modalitiesprofound across all developmental modalitiesIrritabilityyesyesyesOptic nerve hypoplasiayesyesnoCataractsnononoVisual impairmentcortical VIcortical VIcortical VIDysmorphismdepressed nasal bridgelow set posteriorly rotated earssquare nasal tipepicanthic foldsmild micrognathiamild retrognathia2-3 toe syndactylydepressed nasal bridgelarge earssquare nasal tipepicanthic foldsmild micrognathiamild retrognathia2-3 toe syndactylydorsal foot fat padscoarse facial featuresbitemporal narrowingprominent earstriangular faciesGenitalsnormalbilateral cryptorchidismhypospadiasCardiac malformationsnonobicuspid aortic valveGastrointestinalIUGR with FTTPEG feedsconstipationIUGR with FTTPEG feedsconstipationIUGR with FTTPEG feedsconstipationSkeletalthin gracile bonesfixed flexion deformity kneesthin gracile bonesfixed flexion deformity kneesfixed flexion deformities in elbowsSkindry skinphotosensitivitylack of hair pigment on LM/EMdry skinphotosensitivitylack of hair pigment on LM/EMdry skinphotosensitivitySleep cyclepoor sleep initiationpoor sleep initiationpoor sleep initiation and maintenanceCholesterol2.5 (3–5.5 mmol/L)2.8 (3–5.5 mmol/L)2.7 (3–5.5 mmol/L)Triglyceride1.1 (0.55–2.0 mmol/L)1.6 (0.55–2.0 mmol/L)0.8 (0.55–2.0 mmol/L)HDL-C0.7 (0.9–2.2 mmol/L)1.2 (0.9–2.2 mmol/L)1.06 (0.9–2.2 mmol/L)LDL-C1.3 (2.0–3.4 mmol/L)0.8 (2.0–3.4 mmol/L)1.3 (2.0–3.4 mmol/L)VLDL-C0.5 (0.1–20.65 mmol/L)0.7 (0.1–20.65 mmol/L)not performedPlasma total farnesol1.5, 1.6 (<0.12 μmol/L)1.7, 3.9 (<0.12 μmol/L)not performedPlasma squalene0.81, 0.93 (0.36–1.04 μmol/L)0.17, 0.37 (0.36–1.04 μmol/L)not performedMolecularcompound heterozygous mutations: chr8(GRCh37): g. 11667760-11787743, maternal; chr8(GRCh37): g.11689003_11689004delinsAG; NM_001287742.1 (FDFT1): c.880-24_880-23delinsAG, paternalcompound heterozygous mutations: chr8(GRCh37): g. 11667760-11787743, maternal; chr8(GRCh37): g.11689003_11689004delinsAG; NM_001287742.1 (FDFT1): c.880-24_880-23delinsAG, paternalhomozygous mutation: chr8(GRCh37): g.11660095_11660110del; NM_001287742.1: c.-75+131_-75+146delAbbreviations: IUGR, intra-uterine growth retardation; PEG, percutaneous endoscopic gastrostomy; FTT, failure to thrive; LM/EM, light microscopy and electroelectron microscopy. Open table in a new tab Figure 3Urine Metabolite ProfilesShow full caption(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).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Abbreviations: IUGR, intra-uterine growth retardation; PEG, percutaneous endoscopic gastrostomy; FTT, failure to thrive; LM/EM, light microscopy and electroelectron microscopy. (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 affected individuals and their unaffected parents were subjected to whole-exome sequencing (WES). Informed consent for genetic testing was obtained for all individuals under protocols approved by the Royal Children’s Hospital and Health Service Ethics Committee and Sydney Children’s Hospitals Network Human Research Ethics Committee. Assuming a recessive mode of inheritance, prioritization of variants revealed compound heterozygous variants affecting FDFT1, encoding the SS enzyme, in the sibship (individuals 1 and 2): a maternally inherited 120 kb deletion (chr8(GRCh37):g.11667760–11787743), resulting in loss of exons 6–10 of FDFT1 and the entire coding sequence of the neighboring CTSB gene (encoding cathepsin B [MIM: 116810], haploinsufficiency for which is asymptomatic in the mother), and a paternally inherited variant GenBank: NM_001287742.1(FDFT1); c.880−24_880−23delinsAG, predicted to create a novel splice acceptor site. The latter prediction was functionally tested using a minigene splice assay, which indeed showed the retention of 22 bp of intron 8 sequence (Figure S2). FDFT1cDNA analysis using RNA isolates generated from fibroblasts of the sibship confirmed the partial splicing defect, showing both normally spliced FDFT1 cDNA and mis-spliced FDFT1 cDNA (Figure S2). Subsequent western blot analysis demonstrated a marked reduction in squalene synthase protein in cultured lymphoblasts and fibroblasts in individuals 1 and 2 (Figures 4B and S2). An even greater reduction was observed when fibroblasts were cultured in lipid-depleted media. While the FDFT1 level is further reduced relative to the control in the LD-FBS (compared to FBS), we hypothesize that the absolute level may not be decreased, but FDFT1 expression in the control is upregulated in LD-FBS. We hypothesize that the residual squalene synthase protein remaining is likely to arise from the correctly spliced paternal allele, which would also explain our observation at cDNA level. In individual 3, no pathogenic bi-allelic variants affecting the coding sequence of FDFT1 could be identified. Interestingly, however, some of the FDFT1 deeper intronic sequence was interpretable from WES data, in allowing the identification of a rare homozygous intronic 16 bp deletion (Chr8(GRCh37):g.11660095_11660110del). The variant was validated using Sanger sequencing in individual 3 and confirmed to be heterozygous in both non-consanguineous parents (Figure S3). Notably, the deletion is absent from our in-house database containing WES data of >15,000 individuals, nor has it been reported in GnomAD (access date October 25, 2017),7Lek M. Karczewski K.J. Minikel E.V. Samocha K.E. Banks E. Fennell T. O’Donnell-Luria A.H. Ware J.S. Hill A.J. Cummings B.B. et al.Exome Aggregation ConsortiumAnalysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Scopus (6551) Google Scholar suggesting that this is a private mutation (Figure S3). The residual variation intolerance score (RVIS) of FDFT1 shows that it is among the 6.5% of human genes most intolerant to functional variation.8Petrovski S. Wang Q. Heinzen E.L. Allen A.S. Goldstein D.B. Genic intolerance to functional variation and the interpretation of personal genomes.PLoS Genet. 2013; 9: e1003709Crossref PubMed Scopus (639) Google Scholar We next determined the functional consequence of the 16 bp intronic deletion in individual 3. FDFT1 exists in 11 different isoforms, encoding 5 different protein variants (Figure S4). Using fetal and adult organ-specific cDNA libraries, we determined the normal pattern for 10/11 isoforms and detected ubiquitous FDFT1 presence in all major organ tissues tested (Figure S5). Next, we tested cDNA generated from a fibroblast cell line of individual 3, as well as from a control individual, for the presence of these FDFT1 isoforms. Whereas all ten isoforms tested were present in the control fibroblast line, only seven of ten were present in individual 3 (Figure S5), and three isoforms remained undetected (GenBank: NM_001287742.1, NM001287743.1, and NM00128774.4; Figure 4C). The addition of cycloheximide (CHX) failed to result in isoform detection (Figure 4C), suggesting that the absence of these isoforms is a consequence of abnormal regulation rather than erroneous splicing degraded by nonsense-mediated RNA decay. Under normal conditions, the absent FDFT1 isoforms are observed in fetal and adult skeletal muscle, as well as in adult brain, spleen, testis, lung, and kidney (Figure S5). In line with the presence of the seven other FDFT1 isoforms, western blot analysis on fibroblasts from individual 3 identified squalene synthase at protein levels comparable to a normal control individual (Figure S6). We next explored the possibility that the 16 bp intronic deletion in FDFT1 generates pathogenicity as a consequence of a regulatory disturbance. Annotation of the chromatic state for FDFT1 indicates that the region containing the 16 bp deletion is predicted to have promoter and/or enhancer effects (Figure S7). To assess the effect of the deletion on the putative promoter activity, two constructs were generated and tested in a luciferase assay: one construct containing the 1,024-bp wild-type promoter sequence and one containing the same fragment but with the 16 bp deletion. Analysis of the wild-type sequence showed that indeed the sequence has promoter capacity (Figure 4D, Table S1). Moreover, the normalized luciferase readout of the construct containing the 16-bp deletion shows a significantly reduced promoter activity sequence (two-tailed t test, p = 2.90 × 10−6), suggesting that the aberrant expression of FDFT1 isoforms in individual 3 may indeed be the consequence of diminished promoter activity due to the homozygous 16 bp deletion (Figure 4D, Table S1). Farnesol and its products exhibit a wide variety of biological activities, including cell growth inhibition, induction of apoptosis, and regulation of bile acid secretion.9Joo J.H. Jetten A.M. Molecular mechanisms involved in farnesol-induced apoptosis.Cancer Lett. 2010; 287: 123-135Crossref PubMed Scopus (140) Google Scholar The primitive streak gives rise to the endoderm and mesoderm in embryonic stem cells (ES). Mouse ES primitive streak development is inhibited by statin medication, which is driven by protein farnesylation.10Okamoto-Uchida Y. Yu R. Miyamura N. Arima N. Ishigami-Yuasa M. Kagechika H. Yoshida S. Hosoya T. Nawa M. Kasama T. et al.The mevalonate pathway regulates primitive streak formation via protein farnesylation.Sci. Rep. 2016; 6: 37697Crossref PubMed Scopus (9) Google Scholar Farnesol-induced apoptosis is associated with ER stress and activation of the unfolded protein response, inhibition of the phosphatidylcholine system, activation of MAP-kinases, and activation of the apoptosome intrinsic mitochondrial-dependent caspases.9Joo J.H. Jetten A.M. Molecular mechanisms involved in farnesol-induced apoptosis.Cancer Lett. 2010; 287: 123-135Crossref PubMed Scopus (140) Google Scholar Evidence is emerging that dysregulation of the mevalonate pathway may be involved in the progression of neurodegeneration in disorders such as Alzheimer disease (MIM: 104300).11Hottman D.A. Li L. Protein prenylation and synaptic plasticity: implications for Alzheimer’s disease.Mol. Neurobiol. 2014; 50: 177-185Crossref PubMed Scopus (40) Google Scholar Cholesterol biosynthesis defects are noted for significant birth malformations.1Waterham H.R. Defects of cholesterol biosynthesis.FEBS Lett. 2006; 580: 5442-5449Crossref PubMed Scopus (87) Google Scholar These are also evidenced in our individuals with FDFT1 disruptive variants (Table 1). Pathogenic mechanisms could involve direct toxicity of accumulated metabolites, abnormal processes that involve farnesyl-pyrophosphate (such as protein farnesylation, Figure 1), or reduced cholesterol moiety attachments to the hedgehog patterning gene family.1Waterham H.R. Defects of cholesterol biosynthesis.FEBS Lett. 2006; 580: 5442-5449Crossref PubMed Scopus (87) Google Scholar Also, tissue-specific analyses of the various FDFT1 isoforms show that at least one isoform (GenBank: NM_001287743.1) is detected in brain, which is absent in individual 3 (Figure S5), and could potentially explain the severe neurodevelopmental disorder observed. Importantly, Fdft1-null mice demonstrate embryonic lethality at day 12.5 in conjunction with growth restriction and neurodevelopmental disorders.12Tozawa R. Ishibashi S. Osuga J. Yagyu H. Oka T. Chen Z. Ohashi K. Perrey S. Shionoiri F. Yahagi N. et al.Embryonic lethality and defective neural tube closure in mice lacking squalene synthase.J. Biol. Chem. 1999; 274: 30843-30848Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar The fact that the FDFT1 variants in individuals 1, 2, and 3 are compatible with life may be explained by the fact that all individuals have some form of residual FDFT1 activity, either resulting from the diminished levels of correctly spliced FDFT1 in individuals 1 and 2, or alternatively, by functional compensation for disrupted regulation in individual 3. In conclusion, we describe squalene synthase deficiency due to pathogenic variants in FDFT1 leading to altered splicing and transcriptional deregulation of the FDFT1 isoforms. The clinical phenotype resembles other known cholesterol biosynthesis defects. The accumulation of farnesyl pyrophosphate in this disorder initiates a complex metabolic cascade involving glucuronidation, hydroxylation, and oxidation to shorter chain molecules. Our cohort exhibits a urine metabolite profile which is an important diagnostic indicator and provides insight into the important role of FDFT1 in embryogenesis and morphogenesis. The authors declare no competing financial interests. The authors would, first and foremost, like to thank the families, without whose participation this work would not have been possible. This work was supported by the Kevin Milo Trust and internal research funds at the Children’s Hospital at Westmead. The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. Download .pdf (1.48 MB) Help with pdf files Document S1. Figures S1–S7, Table S1, Supplemental Case Reports, and Supplemental Methods dbSNP, https://www.ncbi.nlm.nih.gov/projects/SNP/DECIPHER, https://decipher.sanger.ac.uk/GenBank, https://www.ncbi.nlm.nih.gov/genbank/gnomAD Browser, http://gnomad.broadinstitute.org/MutationTaster, http://www.mutationtaster.org/NIST Standard Reference Databases: Analytical Chemistry, http://www.nist.gov/srd/analy.cfmOMIM, http://www.omim.org/PolyPhen-2, http://genetics.bwh.harvard.edu/pph2/Primer3, http://bioinfo.ut.ee/primer3SIFT, http://sift.bii.a-star.edu.sg/UCSC Genome Browser, https://genome.ucsc.edu" @default.
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• W2808114064 title "Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis" @default.
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