Alternative titles; symbols
HGNC Approved Gene Symbol: DHDDS
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38) : 1:26,432,321-26,471,306 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11 | ?Congenital disorder of glycosylation, type 1bb | 613861 | Autosomal recessive | 3 |
| Developmental delay and seizures with or without movement abnormalities | 617836 | Autosomal dominant | 3 | |
| Retinitis pigmentosa 59 | 613861 | Autosomal recessive | 3 |
Dehydrodolichyl diphosphate (dedol-PP) synthase catalyzes cis-prenyl chain elongation to produce the polyprenyl backbone of dolichol, a glycosyl carrier lipid required for the biosynthesis of several classes of glycoproteins (summary by Endo et al., 2003).
By searching databases for sequences similar to E. coli undecaprenyl diphosphate synthase (UPS) and S. cerevisiae dedol-PP synthase, followed by RT-PCR of a testis cDNA library, Endo et al. (2003) cloned DHDDS, which they designated HDS. The deduced 333-amino acid DHDDS protein contains all 5 regions conserved among cis-prenyl chain-elongating enzymes in several eukaryotic and prokaryotic species. DHDDS shares 41.8% homology with yeast dedol-PP synthase and 37.6% homology with E. coli UPS. Northern blot analysis detected high DHDDS expression in testis and kidney, with lower levels in heart, spleen, and thymus.
Zelinger et al. (2011) performed RT-PCR analysis in 21 human tissues and observed ubiquitous expression of DHDDS, with a band of higher intensity in the retinal sample compared to other tissues. The analysis confirmed the expression of the full-length transcript in the retina as well as 3 alternatively spliced variants, 2 of which were in-frame and likely to encode a protein.
Endo et al. (2003) determined that the DHDDS gene contains 8 coding exons and spans more than 37 kb. Zelinger et al. (2011) noted that the DHDDS gene contains 9 exons and that exon 1 is noncoding.
By genomic sequence analysis, Endo et al. (2003) mapped the DHDDS gene to chromosome 1p35.
By genomic sequence analysis, Zelinger et al. (2011) mapped the DHDDS gene to chromosome 1p36.11.
By in vitro assay, Endo et al. (2003) demonstrated cis-prenyltransferase activity in DHDDS-transformed yeast membrane fractions incubated with radiolabeled isopentenyl diphosphate and farnesyl diphosphate as substrates. Thin-layer chromatography detected synthesis of high levels of dolichols with major chain lengths of C90, C95, and C100, consistent with dolichols isolated from human tissues.
By yeast 2-hybrid screening of a human testis cDNA library, Kharel et al. (2004) identified NPC2 (601015) as a DHDDS-interacting protein. They confirmed the interaction by coimmunoprecipitation analysis.
Harrison et al. (2011) identified NGBR (NUS1; 610463) as an endoplasmic reticulum (ER) protein whose C-terminal domain could face either the ER lumen or the cytosol. They found that, when the C-terminal domain was oriented toward the cytosol, NGBR interacted with and stabilized CIT. Knockdown of NGBR in human endothelial/epithelial hybridomas dramatically reduced the content of lipid-linked oligosaccharides, total free glycan pools, and protein N-glycosylation, and it reduced microsomal CIT activity. Reciprocal coimmunoprecipitation analysis revealed that epitope-tagged NGBR and CIT interacted via the C-terminal domain of NGBR. Overexpression and knockdown studies revealed that NGBR and CIT stabilized each other.
Zelinger et al. (2011) performed immunohistochemical analysis of the human retina with anti-DHDDS antibodies and observed intense labeling of the cone and rod photoreceptor inner segments.
Retinitis Pigmentosa 59
In 3 affected sibs from an Ashkenazi Jewish family with retinitis pigmentosa (RP59; 613861), in whom mutation in all known RP genes had been excluded, Zuchner et al. (2011) performed whole-exome sequencing and identified homozygosity for a missense mutation in the DDHS gene (K42E; 608172.0001) that was not present in their unaffected sib. The unaffected parents were heterozygous for the mutation, which was detected in heterozygosity in 8 of 717 Ashkenazi Jewish controls but was not found in 6,977 confirmed non-Ashkenazi white controls; the variant was also found once in 5,893 additional white controls for whom genomewide genotype data were not available. Zuchner et al. (2011) stated that E42K likely arose from an ancestral founder.
In 15 (12%) of 123 Ashkenazi Jewish (AJ) probands with RP, Zelinger et al. (2011) identified homozygosity for the K42E founder mutation. The K42E mutation was found in heterozygosity in 1 of 322 ethnically matched controls, indicating a carrier frequency of 0.3% in the AJ population, but was not detected in an additional set of 109 AJ patients with RP, in 20 AJ patients with other inherited retinal diseases, or in 70 patients with retinal degeneration of other ethnic origins.
Wen et al. (2013) found that RP patients with the K42E DHDDS mutation had increased levels of shortened plasma and urinary dolichols compared to controls, and they suggested that this assay could serve as a biomarker.
Congenital Disorder of Glycosylation Type 1bb
In a male infant with fatal congenital disorder of glycosylation type 1bb (CDG1BB; see 613861), Sabry et al. (2016) identified compound heterozygosity for nonsense (608172.0004) and splice site (608172.0005) mutations in the DHDDS gene, which segregated with the disorder in the family. Patient cells showed 20 to 25% residual normal DHDDS mRNA, likely from the leaky splice site mutation, and 35% residual DHDDS activity compared to controls. Laboratory studies showed hypoglycosylation of plasma proteins. Patient fibroblasts showed increased levels of truncated dolichol-linked oligosaccharides, and microsomes derived from the patient showed low levels of dolichol-phosphate. The patient also carried the homozygous F304S polymorphism in the ALG6 gene (604566), which is considered to be a disease modifier that exacerbates the disease in patients with mutations in other genes of the glycosylation pathway. Sabry et al. (2016) noted that the phenotype was much more severe than that reported in patients with RP59.
Developmental Delay and Seizures with or without Movement Abnormalities
In 5 unrelated patients with developmental delay and seizures with or without movement abnormalities (DEDSM; 617836), Hamdan et al. (2017) identified 2 different de novo heterozygous missense mutations in the DHDDS gene (R37H, 608172.0002 and R211Q, 608172.0003). The mutations were found by whole-exome or whole-genome sequencing of several cohorts of patients with developmental delay and epilepsy. Studies of patient cells and functional studies of the variants were not performed, but Hamdan et al. (2017) postulated a gain-of-function or dominant-negative effect.
By morpholino-knockdown of Dhdds in zebrafish, Zuchner et al. (2011) observed failure to exhibit the typical escape response to light on-off switches, and microscopic examination of the morphant retina revealed that photoreceptor outer segments were very short or completely missing; in addition, one-third of zebrafish morphants had smaller eyes and a slight ventral flexion to the body axis.
In 3 affected sibs from an Ashkenazi Jewish family with retinitis pigmentosa (RP59; 613861), Zuchner et al. (2011) identified homozygosity for a 124A-G transition in exon 3 of the DHDDS gene, resulting in a lys42-to-glu (K42E) substitution at a highly conserved residue located close to the catalytic center and the substrate binding site for farnesyl phosphate. The unaffected parents were heterozygous for the mutation, which was also detected in heterozygosity in 8 of 717 Ashkenazi Jewish controls but not found in 6,977 confirmed non-Ashkenazi white controls; the variant was also found once in 5,893 additional white controls for whom genomewide genotype data were not available.
In 20 Ashkenazi Jewish patients with RP from 15 families, Zelinger et al. (2011) identified homozygosity for the E42K founder mutation in exon 3 of the DHDDS gene.
Sabry et al. (2016) demonstrated that the K42E variant was unable to complement the growth defect in yeast lacking the ortholog RER2, consistent with a loss of function. Yeast transfected with the mutation also showed hypoglycosylation of carboxypeptidase Y. These defects could be restored with wildtype DHDDS.
In 2 unrelated patients (indvSG and HSJ0762) with developmental delay and seizures with or without movement abnormalities (DEDSM; 617836), Hamdan et al. (2017) identified a de novo heterozygous c.110G-A transition (c.110G-A, NM_024887.3) in the DHDDS gene, resulting in an arg37-to-his (R37H) substitution at a conserved residue in the catalytic domain. The mutation, which was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a gain-of-function or dominant-negative effect.
In 3 unrelated patients (indvEF, MDB31882, and indvNCJ) with developmental delay and seizures with or without movement abnormalities (DEDSM; 617836), Hamdan et al. (2017) identified a de novo heterozygous c.632G-A transition (c.632G-A, NM_024887.3) in the DHDDS gene, resulting in an arg211-to-gln (R211Q) substitution at a conserved residue in the IPP domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against public databases, including the Exome Variant Server, 1000 Genomes Project, and ExAC. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a gain-of-function or dominant-negative effect.
In a male infant with fatal congenital disorder of glycosylation type 1bb (CDG1BB; see 613861), Sabry et al. (2016) identified compound heterozygous mutations in the DHDDS gene: a c.192G-A transition (c.192G-A, NM_020438) in exon 4, resulting in a trp74-to-ter (W74X) substitution, and an A-to-G transition in intron 5 (c.441-24A-G; 608172.0005), predicted to result in a splicing abnormality, a frameshift, and premature termination (Cys148GlufsTer11). The mutations, which were found by sequencing of genes required for dolichol biosynthesis, segregated with the disorder in the family. In vitro functional studies showed that the W74X variant was unable to complement the growth defect in yeast lacking the ortholog RER2. Yeast transfected with the mutation also showed hypoglycosylation of carboxypeptidase Y. These defects could be restored with wildtype DHDDS. Laboratory studies showed hypoglycosylation of plasma proteins. Patient fibroblasts showed increased levels of truncated dolichol-linked oligosaccharides, and microsomes derived from the patient showed low levels of dolichol-phosphate. The biochemical findings were consistent with congenital disorder of glycosylation type I. Patient cells showed 20 to 25% residual normal DHDDS mRNA, likely from the leaky splice site mutation, and 35% residual DHDDS activity compared to controls. The patient also carried the homozygous F304S polymorphism in the ALG6 gene (604566), which is considered to be a disease modifier that exacerbates the disease in patients with mutations in other genes of the glycosylation pathway.
For discussion of the A-to-G transition (c.441-24A-G, NM_020438) in intron 5 of the DHDDS gene that was found in compound heterozygous state in a patient with congenital disorder of glycosylation type 1bb (CDG1BB; see 613861) by Sabry et al. (2016), see 608172.0004.
Endo, S., Zhang, Y.-W., Takahashi, S., Koyama, T. Identification of human dehydrodolichyl diphosphate synthase gene. Biochim. Biophys. Acta 1625: 291-295, 2003. [PubMed: 12591616] [Full Text: https://doi.org/10.1016/s0167-4781(02)00628-0]
Hamdan, F. F., Myers, C. T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A. D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., Dobrzeniecka, S., Meloche, C., and 95 others. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am. J. Hum. Genet. 101: 664-685, 2017. [PubMed: 29100083] [Full Text: https://doi.org/10.1016/j.ajhg.2017.09.008]
Harrison, K. D., Park, E. J., Gao, N., Kuo, A., Rush, J. S., Waechter, C. J., Lehrman, M. A., Sessa, W. C. Nogo-B receptor is necessary for cellular dolichol biosynthesis and protein N-glycosylation. EMBO J. 30: 2490-2500, 2011. [PubMed: 21572394] [Full Text: https://doi.org/10.1038/emboj.2011.147]
Kharel, Y., Takahashi, S., Yamashita, S., Koyama, T. In vivo interaction between the human dehydrodolichyl diphosphate synthase and the Niemann-Pick C2 protein revealed by a yeast two-hybrid system. Biochem. Biophys. Res. Commun. 318: 198-203, 2004. [PubMed: 15110773] [Full Text: https://doi.org/10.1016/j.bbrc.2004.04.007]
Sabry, S., Vuillaumier-Barrot, S., Mintet, E., Fasseu, M., Valayannopoulos, V., Heron, D., Dorison, N., Mignot, C., Seta, N., Chantret, I., Dupre, T., Moore, S. E. H. A case of fatal type I congenital disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity. Orphanet J. Rare Dis. 11: 84, 2016. Note: Electronic Article. [PubMed: 27343064] [Full Text: https://doi.org/10.1186/s13023-016-0468-1]
Wen, R., Lam, B. L., Guan, Z. Aberrant dolichol chain lengths as biomarkers for retinitis pigmentosa caused by impaired dolichol biosynthesis. J. Lipid Res. 54: 3516-3522, 2013. [PubMed: 24078709] [Full Text: https://doi.org/10.1194/jlr.M043232]
Zelinger, L., Banin, E., Obolensky, A., Mizrahi-Meissonnier, L., Beryozkin, A., Bandah-Rozenfeld, D., Frenkel, S., Ben-Yosef, T., Merin, S., Schwartz, S. B., Cideciyan, A. V., Jacobson, S. G., Sharon, D. A missense mutation in DHDDS, encoding dehydrodolichyl diphosphate synthase, is associated with autosomal-recessive retinitis pigmentosa in Ashkenazi Jews. Am. J. Hum. Genet. 88: 207-215, 2011. [PubMed: 21295282] [Full Text: https://doi.org/10.1016/j.ajhg.2011.01.002]
Zuchner, S., Dallman, J., Wen, R., Beecham, G., Naj, A., Farooq, A., Kohli, M. A., Whitehead, P. L., Hulme, W., Konidari, I., Edwards, Y. J. K., Cai, G. Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa. Am. J. Hum. Genet. 88: 201-206, 2011. [PubMed: 21295283] [Full Text: https://doi.org/10.1016/j.ajhg.2011.01.001]