Alternative titles; symbols
HGNC Approved Gene Symbol: FDFT1
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38) : 8:11,795,582-11,839,298 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p23.1 | Squalene synthase deficiency | 618156 | Autosomal recessive | 3 |
Farnesyldiphosphate farnesyltransferase (EC 2.5.1.21), or squalene synthase, catalyzes the conversion of trans-farnesyldiphosphate to squalene, the first specific step in the cholesterol biosynthetic pathway (Shechter et al., 1994).
Jiang et al. (1993) isolated a cDNA encoding human squalene synthase.
Guan et al. (1995) cloned and characterized the promoter of the FDFT1 gene. A 69-bp sequence positioned 131 bp 5-prime to the transcription start site conferred transcriptional competence and sterol regulation. Sequence analysis of this region showed that it contains a sterol regulatory element-1 (SRE1) previously identified in other sterol-regulated genes and 2 potential NF1-binding sites.
Coman et al. (2018) reported that the FDFT1 gene contains 10 exons producing 11 different isoforms that encode 5 different proteins.
To map the FDFT1 gene, Shechter et al. (1994) first isolated a yeast artificial chromosome (YAC) containing the FDFT1 gene. They then used fluorescence in situ hybridization with the YAC to map the gene to chromosome 8. Assignment to chromosome 8 was confirmed by PCR analysis of a somatic cell hybrid containing human chromosome 8. Use of a somatic cell hybrid regional mapping panel dividing chromosome 8 into several fragments localized the gene to chromosome 8pter-p21. Fractional length analysis of the FISH mapping placed the signal generated with this YAC at chromosome 8p23.1-p22.
Do et al. (2009) reviewed the role of squalene synthase in cholesterol biosynthesis, including regulation of cellular and plasma cholesterol levels, noting that it is responsible for the flow of metabolites into either the sterol or nonsterol branch of the pathway.
In a study of the breakpoint at 8p23.1 associated with the inversion 8 chromosome found in at least 1 parent of all Rec(8) syndrome (179613) individuals, Patterson et al. (1995) found that the clones contained at least the 5-prime coding region of the FDFT1 gene, which they referred to as DGPT.
By positional cloning and genotyping in Shumiya cataract rats, Mori et al. (2006) identified hypomorphic mutations in the Lss gene (600909) and the Fdft1 gene, as well as a null mutation in Lss. Cataract onset was associated with the specific combination of Lss and Fdft1 mutant alleles that decreased cholesterol levels in cataractous lenses to about 57% of normal. Mori et al. (2006) concluded that cholesterol insufficiency may cause the deficient proliferation of lens epithelial cells in Shumiya cataract rats, resulting in the loss of homeostatic epithelial cell control of the underlying fiber cells and ultimately cataractogenesis.
Coman et al. (2018) reported 3 children with squalene synthase deficiency (SQSD; 618156) from 2 families with homozygous or compound heterozygous mutations in the FDFT1 gene (184420.0001-184420.0003). The clinical phenotype resembled that of other cholesterol biosynthesis defects (e.g., Smith-Lemi-Opitz syndrome, 270400).
In 2 sibs with squalene synthase deficiency (SQSD; 618156), Coman et al. (2018) identified compound heterozygosity for mutations in the FDFT1 gene. The maternal allele carried a 120-kb deletion (chr8.11667760-11787743, GRCh37) encompassing exons 6 through 10 of the FDFT1 gene and all of the cathepsin B gene (CTSB; 116810). The paternal allele carried a TC deletion/AG insertion in intron 8 (184420.0002) that created a novel splice acceptor site and resulted in the retention of 22 bp of intron 8 sequence. Western blot analysis showed marked reduction in FDFT1 protein in patient-derived lymphoblasts and fibroblasts; there was even more dramatic reduction in fibroblasts grown in lipid-free media.
For discussion of the TC deletion/AG insertion in intron 8 of the FDFT1 gene (c.880-24_880-23delinsAG, NM_001287742.1) that was found in compound heterozygous state in 2 sibs with squalene synthase deficiency (SQSD; 618156) by Coman et al. (2018), see 184420.0001.
In a patient born of a nonconsanguineous union with squalene synthase deficiency (SQSD; 618156), Coman et al. (2018) identified homozygosity for a 16-bp deep intronic deletion (chr8.11660095_11660110del, GRCh37). This deletion was detected by whole-exome sequencing and confirmed by Sanger sequencing, and was inherited from both parents. The mutation was not present in the gnomAD database or among more than 15,000 in-house exomes. Three of the 11 isoforms of FDFT1 (NM_001287742.1, NM_001287743.1, and NM_00128774.4) were undetected in a patient-derived fibroblast cell line. The absent isoforms are normally detected in fetal and adult skeletal muscle and in adult brain, spleen, testis, lung, and kidney. Addition of cycloheximide failed to result in isoform detection, suggesting that the absence of these isoforms was due to abnormal regulation rather than erroneous splicing degraded by nonsense-mediated decay. Luciferase assay showed significantly reduced promoter activity from a fragment carrying the deletion compared to a wildtype fragment.
Coman, D., Vissers, L. E. L. M., Riley, L. G., Kwint, M. P., Hauck, R., Koster, J., Geuer, S., Hopkins, S., Hallinan, B., Sweetman, L., Engelke, U. F. H., Burrow, T. A., Cardinal, J., McGill, J., Inwood, A., Gurnsey, C., Waterham, H. R., Christodoulou, J., Wevers, R. A., Pitt, J. Squalene synthase deficiency: clinical, biochemical, and molecular characterization of a defect in cholesterol biosynthesis. Am. J. Hum. Genet. 103: 125-130, 2018. [PubMed: 29909962] [Full Text: https://doi.org/10.1016/j.ajhg.2018.05.004]
Do, R., Kiss, R. S., Gaudet, D., Engert, J. C. Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway. Clin. Genet. 75: 19-29, 2009. [PubMed: 19054015] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01099.x]
Guan, G., Jiang, G., Koch, R. L., Shechter, I. Molecular cloning and functional analysis of the promoter of the human squalene synthase gene. J. Biol. Chem. 270: 21958-21965, 1995. [PubMed: 7665618] [Full Text: https://doi.org/10.1074/jbc.270.37.21958]
Jiang, G., McKenzie, T. L., Conrad, D. G., Shechter, I. Transcriptional regulation by lovastatin and 25-hydroxycholesterol in HepG2 cells and molecular cloning and expression of the cDNA for the human hepatic squalene synthase. J. Biol. Chem. 268: 12818-12824, 1993. [PubMed: 7685352]
Mori, M., Li, G., Abe, I., Nakayama, J., Guo, Z., Sawashita, J., Ugawa, T., Nishizono, S., Serikawa, T., Higuchi, K., Shumiya, S. Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat. J. Clin. Invest. 116: 395-404, 2006. [PubMed: 16440058] [Full Text: https://doi.org/10.1172/JCI20797]
Patterson, D., Sujansky, E., Hart, I., Bleskan, J., Walton, K., Giang, J., Shechter, I. Recombinant 8 syndrome breakpoint analysis. (Abstract) Am. J. Hum. Genet. 57: A91 only, 1995.
Shechter, 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 20: 116-118, 1994. [PubMed: 8020937] [Full Text: https://doi.org/10.1006/geno.1994.1135]