Alternative titles; symbols
HGNC Approved Gene Symbol: SC5D
SNOMEDCT: 719257008;
Cytogenetic location: 11q23.3-q24.1 Genomic coordinates (GRCh38): 11:121,292,771-121,313,410 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3-q24.1 | Lathosterolosis | 607330 | Autosomal recessive | 3 |
Sterol C5-desaturase (EC 1.3.3.2), or SC5D, is involved in the biosynthesis of cholesterol, specifically catalyzing the conversion of lathosterol into 7-dehydrocholesterol.
Based on high homology between a human fetal brain cDNA and the ERG3 gene of Candida glabrata, Matsushima et al. (1996) identified a putative sterol C5-desaturase. DNA sequencing revealed that the open reading frame of the gene predicts a 236-amino acid protein. Northern blot analysis detected a 2.4-kb transcript in all tissues examined. In addition, an 8.0-kb transcript was seen in almost all tissues.
By screening a sequence database for homology with S. cerevisiae SC5D, followed by PCR, Nishi et al. (2000) cloned SC5D from a liver cDNA library. They found that the liver sequence contains more than 200 nucleotides that are missing from the brain sequence cloned by Matsushima et al. (1996). The deduced liver protein contains 299 amino acids and is predicted to be an integral membrane protein with 4 to 5 membrane-spanning regions. It has 10 evolutionarily conserved histidines that may coordinate a nonheme iron within the catalytic center. SC4DL shares 83.6% amino acid identity with mouse Sc4dl.
Nishi et al. (2000) confirmed enzymatic activity in microsomes prepared from yeast transformed with SC5D. Transformed cells produced 7-dehydrocholesterol in the presence of lathosterol. Transfection of SC5D also functionally complemented Sc5d-deficient yeast cells.
Sugawara et al. (2001) determined that the SC5D gene contains 5 exons.
Matsushima et al. (1996) mapped the SC5DL gene to chromosome 11q23.3 by fluorescence in situ hybridization.
Brunetti-Pierri et al. (2002) reported a female patient with deficiency of SC5D, which they designated lathosterolosis (LATHOS; 607330) because of the increased levels of lathosterol in the patient's plasma and cells. They found that the patient was compound heterozygous for 2 missense mutations in the SC5D gene (R29G, 602286.0001; G211D, 602286.0002). The mutations segregated with the phenotype in the family.
In a patient with lathosterolosis, previously reported by Parnes et al. (1990), Krakowiak et al. (2003) identified a homozygous mutation in the SC5D gene (Y46S; 602286.0003). The parents were heterozygous for the mutation.
In a child with lathosterolosis, Ho et al. (2014) identified compound heterozygosity for 2 missense mutations in the SC5D gene (D210E, 602286.0004 and K148E, 602286.0005). Each parent was heterozygous for one of the mutations.
In a 10-year-old boy with lathosterolosis, Anderson et al. (2019) identified compound heterozygous mutations in the SC5D gene: the previously identified D210E mutation and a novel missense mutation (P160R; 602286.0006). Each parent was heterozygous for one of the mutations. The mutations were identified by next-generation sequencing of a panel of genes associated with congenital or childhood cataracts.
Krakowiak et al. (2003) disrupted the mouse lathosterol 5-desaturase gene (Sc5d). Sc5d -/- pups were stillborn, had elevated lathosterol and decreased cholesterol levels, craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d -/- mice were consistent with impaired hedgehog signaling and appeared to be a result of decreased cholesterol rather than increased lathosterol.
In a female patient with lathosterolosis (LATHOS; 607330), Brunetti-Pierri et al. (2002) identified compound heterozygosity for 2 missense mutations in the SC5D gene: a c.86G-A transition, resulting in an arg29-to-gln (R29Q) substitution, and a c.632G-A transition, resulting in a gly211-to-asp substitution (G211D; 602286.0002) at a highly conserved residue. In a previous pregnancy in this family, a female fetus was aborted at 22 weeks' gestation because of multiple malformations identified on routine ultrasound. Each parent was heterozygous for one of the mutations and an unaffected brother was heterozygous for the R29Q mutation. Rossi et al. (2007) reported that the fetus sib was also found to be compound heterozygous for the mutations.
For discussion of the c.632G-A transition in the SC5D gene, resulting in a gly211-to-asp (G211D) substitution, that was found in compound heterozygous state in a patient with lathosterolosis (LATHOS; 607330) by Brunetti-Pierri et al. (2002), see 602286.0001.
In a patient with lathosterolosis (LATHOS; 607330), Krakowiak et al. (2003) identified a homozygous c.137A-C transversion in the SC5D gene, resulting in a tyr46-to-ser (Y46S) substitution. The patient was initially described by Parnes et al. (1990) as having atypical Smith-Lemli-Opitz syndrome (270400) with mucolipidosis, but biochemical and molecular analyses confirmed the diagnosis of lathosterolosis. The parents were heterozygous for the mutation. Patient fibroblasts showed deficient SC5D enzymatic activity.
In a child with lathosterolosis (LATHOS; 607330), Ho et al. (2014) identified compound heterozygosity for 2 mutations in the SC5D gene: a c.630C-A transversion (c.630C-A, NM_006918.4), resulting in an asp210-to-glu (D210E) substitution, and a c.442A-G transition, resulting in a lys148-to-glu (K148E; 602286.0005) substitution. Each parent was heterozygous for one of the mutations. Neither variant was present in the dbSNP database or in 150 normal controls. Patient fibroblasts grown on lipid-depleted medium showed elevated concentrations of lathosterol and its precursor, 8,9-cholestenol. Fibroblast staining for filipin showed a 'variant' cholesterol storage pattern, and perinuclear cholesterol content was moderately elevated.
In a 10-year-old boy with lathosterolosis, Anderson et al. (2019) identified compound heterozygosity for 2 mutations in the SC5D gene: the D210E mutation and a c.479C-G transversion resulting in a pro160-to-arg (P160R; 602286.0006) substitution. Both mutations occur at highly conserved residues. Each parent was heterozygous for one of the mutations. The mutations were identified by next-generation sequencing of a panel of genes associated with congenital or childhood cataracts. Both variants were rare in the gnomAD database.
For discussion of the c.442A-G transition (c.442A-G, NM_006918.4) in the SC5D gene, resulting in a lys148-to-glu (K148E) substitution, that was found in compound heterozygous state in a patient with lathosterolosis (LATHOS; 607330) by Ho et al. (2014), see 602286.0004.
For discussion of the c.479C-G transversion in the SC5D gene, resulting in a pro160-to-arg (P160R) substitution, that was found in compound heterozygous state in a patient with lathosterolosis (LATHOS; 607330) by Anderson et al. (2019), see 602286.0004.
Anderson, R., Rust, S., Ashworth, J., Clayton-Smith, J., Taylor, R. L., Clayton, P. T., Morris, A. A. M. Lathosterolosis: a relatively mild case with cataracts and learning difficulties. JIMD Rep. 44: 79-84, 2019. [PubMed: 30097991] [Full Text: https://doi.org/10.1007/8904_2018_127]
Brunetti-Pierri, N., Corso, G., Rossi, M., Ferrari, P., Balli, F., Rivasi, F., Annunziata, I., Ballabio, A., Russo, A. D., Andria, G., Parenti, G. Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3-beta-hydroxysteroid-delta(5)-desaturase. Am. J. Hum. Genet. 71: 952-958, 2002. Note: Erratum: Am. J. Hum. Genet. 73: 445 only, 2003. [PubMed: 12189593] [Full Text: https://doi.org/10.1086/342668]
Ho, A. C. C., Fung, C. W., Siu, T. S., Ma, O. C. K., Lam, C. W., Tam, S., Wong, V. C. N. Lathosterolosis: a disorder of cholesterol biosynthesis resembling Smith-Lemli-Opitz syndrome. JIMD Rep. 12: 129-134, 2014. [PubMed: 24142275] [Full Text: https://doi.org/10.1007/8904_2013_255]
Krakowiak, P. A., Wassif, C. A., Kratz, L., Cozma, D., Kovarova, M., Harris, G., Grinberg, A., Yang, Y., Hunter, A. G. W., Tsokos, M., Kelley, R. I., Porter, F. D. Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum. Molec. Genet. 12: 1631-1641, 2003. [PubMed: 12812989] [Full Text: https://doi.org/10.1093/hmg/ddg172]
Matsushima, M., Inazawa, J., Takahashi, E., Suzumori, K., Nakamura, Y. Molecular cloning and mapping of a human cDNA (SC5DL) encoding a protein homologous to fungal sterol-C5-desaturase. Cytogenet. Cell Genet. 74: 252-254, 1996. [PubMed: 8976377] [Full Text: https://doi.org/10.1159/000134427]
Nishi, S., Nishino, H., Ishibashi, T. cDNA cloning of the mammalian sterol C5-desaturase and the expression in yeast mutant. Biochim. Biophys. Acta 1490: 106-108, 2000. Note: Erratum: Biochim. Biophys. Acta 1494: 211 only, 2000. [PubMed: 10786622] [Full Text: https://doi.org/10.1016/s0167-4781(99)00248-1]
Parnes, S., Hunter, A. G., Jimenez, C., Carpenter, B. F., MacDonald, I. Apparent Smith-Lemli-Opitz syndrome in a child with a previously undescribed form of mucolipidosis not involving the neurons. Am. J. Med. Genet. 35: 397-405, 1990. [PubMed: 2309789] [Full Text: https://doi.org/10.1002/ajmg.1320350317]
Rossi, M., D'Armiento, M., Parisi, I., Ferrari, P., Hall, C. M., Cervasio, M., Rivasi, F., Balli, F., Vecchione, R., Corso, G., Andria, G., Parenti, G. Clinical phenotype of lathosterolosis. Am. J. Med. Genet. 143A: 2371-2381, 2007. [PubMed: 17853487] [Full Text: https://doi.org/10.1002/ajmg.a.31929]
Sugawara, T., Fujimoto, Y., Ishibashi, T. Molecular cloning and structural analysis of human sterol C5 desaturase. Biochim. Biophys. Acta 1533: 277-284, 2001. [PubMed: 11731337] [Full Text: https://doi.org/10.1016/s1388-1981(01)00160-3]