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DHDDS
dehydrodolichyl diphosphate synthase subunit
DHDDS is located on the short (p) arm of chromosome 1, at band 1p36.11. Arm ratio per GRCh38 - banding schematic.
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Overview
DHDDS is located on chromosome 1 and encodes one of two subunits that form dehydrodolichyl diphosphate synthase, an enzyme responsible for synthesising the polyprenyl backbone of dolichol. Dolichol phosphate serves as a lipid carrier that shuttles sugar molecules across cell membranes during the assembly of glycoproteins, which are proteins with attached carbohydrate chains. These glycoproteins perform essential roles in cell signalling, structural support, and immune function.
When both copies of DHDDS carry pathogenic variants, the resulting enzyme dysfunction impairs protein glycosylation throughout the body. This autosomal recessive condition particularly affects tissues with high metabolic demands, including the retina and nervous system. Clinical manifestations typically include vision loss due to retinal degeneration and various neurological features, reflecting the widespread importance of proper glycosylation for cellular function.
What the gene does
The DHDDS protein functions as the catalytic subunit within the dehydrodolichyl diphosphate synthase complex, working alongside its partner subunit NUS1. Together, these proteins catalyse the sequential addition of isoprene units to form the long carbon chain of dolichol, typically containing 16 to 21 isoprene repeats in human cells. This polyisoprenoid synthesis occurs on the cytoplasmic face of the endoplasmic reticulum membrane.
Once synthesised, dolichol undergoes phosphorylation to form dolichol phosphate, which then accepts sugar residues one by one to build an oligosaccharide precursor. This sugar-loaded carrier flips across the endoplasmic reticulum membrane, where the completed oligosaccharide is transferred en bloc onto nascent proteins at specific asparagine residues. This N-linked glycosylation process is essential for proper protein folding, stability, and trafficking. Cells unable to produce adequate dolichol accumulate misfolded proteins and experience endoplasmic reticulum stress, contributing to cellular dysfunction particularly in metabolically active tissues such as photoreceptors and neurons.
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Chromosome location
DHDDS is positioned on the short arm of chromosome 1 at cytogenetic band 1p36.11. The gene spans approximately 23 kilobases of genomic DNA and contains seven exons that encode a 333-amino-acid protein. This chromosomal region, near the telomere of chromosome 1p, contains numerous genes, and deletions encompassing 1p36 are associated with a recognisable contiguous gene deletion syndrome, though isolated DHDDS variants cause a distinct recessive condition.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Pathogenic variants in DHDDS follow an autosomal recessive inheritance pattern, meaning that affected individuals carry alterations in both gene copies. Reported variants include missense changes that impair enzyme catalytic activity as well as nonsense and frameshift variants predicted to cause loss of functional protein. The specific variant combinations influence clinical severity, with some genotypes associated predominantly with retinal disease whilst others produce combined retinal and neurological presentations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.104G>A | p.Gly35Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 59 |
c.109C>A | p.Arg37Ser | Pathogenic | ★★☆☆ | Retinitis pigmentosa 59 |
c.109C>T | p.Arg37Cys | Pathogenic | ★★☆☆ | Retinitis pigmentosa 59 |
c.113G>A | p.Arg38His | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.264_267del | p.Ser88fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 59 |
c.513G>A | p.Trp171Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 59 |
c.517dup | p.Val173fs | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 59 |
c.614G>A | p.Arg205Gln | Pathogenic | ★★☆☆ | Developmental delay and seizures with or without movement abnormalities |
c.632G>A | p.Arg211Gln | Pathogenic | ★★☆☆ | Developmental delay and seizures with or without movement abnormalities |
c.698C>G | p.Pro233Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Retinitis pigmentosa 59 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic DHDDS variants cause a spectrum of conditions unified by defective dolichol synthesis. The most common presentation is retinitis pigmentosa, a progressive retinal degeneration leading to night blindness, peripheral vision loss, and eventual central vision impairment. Some individuals also develop neurological features including intellectual disability, seizures, movement disorders such as dystonia or chorea, and cerebellar signs like ataxia. The age of onset and combination of symptoms vary between families, reflecting the range of functional impairment caused by different variant combinations.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic DHDDS variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
DHDDS appears on multiple NHS England gene panels reflecting its association with diverse clinical presentations. The gene holds green (diagnostic-grade) classification on the Retinal disorders panel, Intellectual disability panel, Early onset or syndromic epilepsy panel, Ataxia and cerebellar anomalies panel, and Childhood onset dystonia, chorea or related movement disorder panel. This multi-panel representation reflects the variable phenotype of DHDDS-related conditions, which may present initially to different specialties depending on whether retinal, epileptic, or movement disorder features predominate. DHDDS is also included in the Developmental Disorders Genotype-to-Phenotype (DDG2P) database, supporting its use in diagnostic genomic testing for children with developmental conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
How is DHDDS-related retinitis pigmentosa inherited?
DHDDS-related conditions follow autosomal recessive inheritance, meaning an affected individual has inherited a pathogenic variant from each parent. Parents who each carry one variant typically have no symptoms themselves but have a 25% chance with each pregnancy of having an affected child.
Can DHDDS variants cause symptoms other than vision loss?
Yes, whilst retinitis pigmentosa is the hallmark feature, some individuals with biallelic DHDDS variants also develop neurological manifestations including intellectual disability, epilepsy, movement disorders, and problems with coordination. The combination and severity of symptoms vary between affected individuals.
Is genetic testing for DHDDS available through the NHS?
DHDDS testing is available through NHS clinical genomic testing for individuals meeting referral criteria on relevant gene panels, including those for retinal disorders, epilepsy, intellectual disability, and movement disorders. A clinical geneticist or specialist can assess eligibility based on an individual's specific symptoms and family history.