Alternative titles; symbols
HGNC Approved Gene Symbol: SRD5A3
SNOMEDCT: 733601006;
Cytogenetic location: 4q12 Genomic coordinates (GRCh38) : 4:55,346,242-55,373,100 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q12 | Congenital disorder of glycosylation, type Iq | 612379 | Autosomal recessive | 3 |
| Kahrizi syndrome | 612713 | Autosomal recessive | 3 |
Uemura et al. (2008) performed a genomewide study of hormone-refractory prostate cancers (HRPC; see 176807) using cDNA expression arrays to identify abnormally expressed transcripts. The SRD5A3 gene, which was identified by the screen, was confirmed by RT-PCR and Northern blot analyses to be upregulated in HRPC cells but to have little, if any, expression in normal adult organs. The deduced 318-amino acid protein shares sequence similarity and a conserved C-terminal region with steroid 5-alpha-reductases SRD5A1 (184753) and SRD5A2 (607306).
Cantagrel et al. (2010) identified SRD5A3 as the human ortholog of yeast Dfg10 and determined that SRD5A3 contains 6 predicted transmembrane domains.
Cantagrel et al. (2010) noted that the SRD5A3 gene contains 5 exons spanning 25.5 kb.
Scott (2008) mapped the SRD5A3 gene to chromosome 4q12 based on an alignment of the SRD5A3 sequence (GenBank AC064824) with the genomic sequence (build 36.2).
Uemura et al. (2008) showed that recombinant SRD5A3 encodes a steroid 5-alpha-reductase that produces the androgen 5-alpha-dihydrotestosterone (DHT) from testosterone. Mutant SRD5A3 proteins with changes in regions known to affect other SRD5 proteins also abrogated SRD5A3 activity. Knockdown of SRD5A3 expression in an HRPC cell line by siRNA resulted in a significant decrease in DHT production and a marked reduction in cell viability. Uemura et al. (2008) concluded that SRD5A3 is associated with DHT production and maintenance of the androgen-androgen receptor activation pathway in HRPC cells and may represent a target for prostate cancer therapy.
Cantagrel et al. (2010) demonstrated the SRD5A3 and the yeast ortholog Dfg10 are necessary for conversion of the alpha-isoprene unit of polyprenol to form dolichol in human, mouse, and yeast, and thus acts as a polyprenol reductase. The findings also indicated that the reduction of polyprenol is the major pathway for dolichol biosynthesis during N-glycosylation. However, cells depleted of SRD5A3 enzyme had some residual dolichol, suggesting the existence of an alternative pathway for de novo dolichol biosynthesis. Cantagrel et al. (2010) did not find evidence that substrates of SRD5A3 are related to steroids, but noted that polyprenols share a common origin with cholesterol, because they are also built from isoprene units. Finally, patients with SRD5A3 deficiency (CDG1Q; 612379) did not have sexual abnormalities, which also suggested that SRD5A3 does not function as a steroid reductase.
By linkage analysis followed by candidate gene sequencing of a family reported by Al-Gazali et al. (2008) with a multisystem disorder characterized by ocular anomalies, mental retardation, cerebellar defects, and biochemical evidence of a congenital disorder of glycosylation type 1 (CDG1Q; 612379), Cantagrel et al. (2010) identified a homozygous mutation in the SRD5A3 gene (611715.0001). Analysis of similarly affected families identified 6 others with homozygous or compound heterozygous SRD5A3 mutations (see, e.g., 611715.0002-611715.0005). Altogether, there were 11 affected children from 7 families. The mutation spectrum was consistent with a loss of function. The phenotype included ocular anomalies, such as coloboma and optic disc atrophy with loss of vision, mental retardation, cerebellar malformations, and coagulation defects.
In 3 sibs, born of consanguineous Iranian parents, with Kahrizi syndrome (KHRZ; 612713) (Kahrizi et al., 2009), Kahrizi et al. (2011) identified a truncating mutation in the SRD5A3 gene (611715.0006). RT-PCR analysis showed missing or reduced expression of the SRD5A3 gene in patient lymphoblastoid cells. The phenotype was characterized by mental retardation, cataracts, coloboma, and kyphosis. However, biochemical studies showed no clear abnormal transferrin mobility in routine testing for CDG. The mutation was identified by array-based exon enrichment and next-generation sequencing.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. They reported members of 2 separate families with Kahrizi syndrome and a congenital disorder of glycosylation who had homozygous mutations in the SRD5A3 gene.
Cantagrel et al. (2010) found that loss of Srd5a3 in mice was embryonic lethal at day E12.5. Affected embryos were smaller than controls, and failed to undergo axial rotation. Asymptomatic heterozygous carriers showed strong gene expression in the yolk sac, eyes, heart, and neural tube. Homozygous mutants often showed dilated hearts and open neural tubes. Transcriptome analysis of homozygous mutant mice embryos showed a 20% upregulation of genes involved in regulation of the unfolded protein response. These findings suggested that SRD5A3 is required for ER protein folding, which is a primary role of N-glycan during development.
In affected members of a consanguineous Emirati family of Baluch origin, previously reported by Al-Gazali et al. (2008), with autosomal recessive congenital disorder of glycosylation type Iq (CDG1Q; 612379), Cantagrel et al. (2010) identified a homozygous molecular arrangement involving the SRD5A3 gene: a 3-bp deletion and a 10-bp insertion (286delCAAinsTGAGTAAGGC) in exon 2, resulting in a predicted stop codon at amino acid 96 in transmembrane domain II. The change was not found in 192 control chromosomes from geographically matched controls. Another affected Emirati family of Baluch origin was also homozygous for this mutation. The phenotype included ocular anomalies, such as coloboma and optic disc atrophy with loss of vision, mental retardation, cerebellar malformations, and coagulation defects.
In affected members of a consanguineous Turkish family with congenital disorder of glycosylation type Iq (CDG1Q; 612379), Cantagrel et al. (2010) identified a homozygous 320G-A transition in the SRD5A3 gene, resulting in a trp107-to-ter (W107X) substitution in the first intracellular loop.
In affected members of a Polish family with congenital disorder of glycosylation type Iq (CDG1Q; 612379), Cantagrel et al. (2010) identified compound heterozygosity for 2 mutations in the SRD5A3 gene: a 424C-T transition, resulting in an arg142-to-ter (R142X) substitution in transmembrane domain II, and a 489C-A transversion, resulting in a tyr163-to-ter (Y163X; 611715.0004) substitution in transmembrane domain IV.
For discussion of the 489C-A transversion in the SRD5A3 gene, resulting in a tyr163-to-ter (Y163X) substitution, that was found in compound heterozygous state in affected members of a family with congenital disorder of glycosylation type Iq (CDG1Q; 612379) by Cantagrel et al. (2010), see 611715.0003.
In affected members of a consanguineous Turkish family with congenital disorder of glycosylation type Iq (CDG1Q; 612379), Cantagrel et al. (2010) identified a homozygous 29C-A transversion in the SRD5A3 gene, resulting in a ser10-to-ter (S10X) substitution near the intracellular N terminus.
In 3 sibs, born of consanguineous Iranian parents, with Kahrizi syndrome (KHRZ; 612713), previously reported by (Kahrizi et al., 2009), Kahrizi et al. (2011) identified a homozygous 1-bp duplication (203dupC) in exon 1 of the SRD5A3 gene, resulting in a frameshift and premature termination. Each unaffected parent and 2 unaffected sibs were heterozygous for the mutation, which was not found in 366 control chromosomes. RT-PCR analysis showed missing or reduced expression of the SRD5A3 gene in patient lymphoblastoid cells. The phenotype was characterized by mental retardation, cataracts, coloboma, and kyphosis. However, biochemical studies showed no clear abnormal transferrin mobility in routine testing for CDG. The mutation was identified by array-based exon enrichment and next-generation sequencing.
Al-Gazali, L., Hertecant, J., Algawi, K., El Teraifi, H., Dattani, M. A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred Emirati family. Am. J. Med. Genet. 146A: 813-819, 2008. [PubMed: 18271001] [Full Text: https://doi.org/10.1002/ajmg.a.32114]
Cantagrel, V., Lefeber, D. J., Ng, B. G., Guan, Z., Silhavy, J. L., Bielas, S. L., Lehle, L., Hombauer, H., Adamowicz, M., Swiezewska, E., De Brouwer, A. P., Blumel, P., and 13 others. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell 142: 203-217, 2010. [PubMed: 20637498] [Full Text: https://doi.org/10.1016/j.cell.2010.06.001]
Kahrizi, K., Hu, C. H., Garshasbi, M., Abedini, S. S., Ghadami, S., Kariminejad, R., Ullmann, R., Chen, W., Ropers, H.-H., Kuss, A. W., Najmabadi, H., Tzschach, A. Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3. Europ. J. Hum. Genet. 19: 115-117, 2011. [PubMed: 20700148] [Full Text: https://doi.org/10.1038/ejhg.2010.132]
Kahrizi, K., Najmabadi, H., Kariminejad, R., Jamali, P., Malekpour, M., Garshasbi, M., Ropers, H. H., Kuss, A. W., Tzschach, A. An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4. Europ. J. Hum. Genet. 17: 125-128, 2009. [PubMed: 18781183] [Full Text: https://doi.org/10.1038/ejhg.2008.159]
Najmabadi, H., Hu. H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992] [Full Text: https://doi.org/10.1038/nature10423]
Scott, A. F. Personal Communication. Baltimore, Md. 1/4/2008.
Uemura, M., Tamura, K., Chung, S., Honma, S., Okuyama, A., Nakamura, Y., Nakagawa, H. Novel 5-alpha-steroid reductase (SRD5A3, type-3) is overexpressed in hormone-refractory prostate cancer. Cancer Sci. 99: 81-86, 2008. [PubMed: 17986282] [Full Text: https://doi.org/10.1111/j.1349-7006.2007.00656.x]