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DHCR24
24-dehydrocholesterol reductase
The DHCR24 gene provides instructions for making an enzyme called 24-dehydrocholesterol reductase, which plays a critical role in the final steps of cholesterol production within the body. The DHCR24 gene is vital for the synthesis of cholesterol, a fat-like substance essential for cell membranes, nerve insulation, hormone production, and embryonic development.
DHCR24 is located on the short (p) arm of chromosome 1, at band 1p32.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The DHCR24 gene encodes an enzyme that facilitates several biochemical transformations yielding cholesterol from precursor molecules. Such conversions are essential during prenatal growth and continue to support cellular architecture and metabolic processes throughout life.
Cholesterol serves multiple roles: it forms a structural element in cell membranes, contributes to the insulating myelin sheath protecting nerve fibres, and provides the starting material for hormone and bile acid synthesis. The enzyme encoded by DHCR24 is integral to maintaining adequate cholesterol levels across different tissues.
What the gene does
The DHCR24 gene directs the synthesis of 24-dehydrocholesterol reductase, an enzyme central to cholesterol biosynthesis. This enzyme participates in at least two distinct pathways for cholesterol production. In one pathway, it performs the terminal conversion of desmosterol to cholesterol.
In another pathway, 24-dehydrocholesterol reductase transforms lanosterol to produce 24,25-dihydrolanosterol, which eventually leads to cholesterol. Cholesterol is indispensable for normal embryonic development, serving as a component of cell membranes and myelin. It also activates the hedgehog signalling pathway, crucial for prenatal development, and is involved in hormone and digestive acid production. Brain cells, unable to access dietary cholesterol, must synthesise their own, underscoring the enzyme's importance in neurological function.
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Chromosome location
The DHCR24 gene is located on the short arm of chromosome 1 at position 1p32.3. This specific genomic location places it within a region that contributes to various cellular processes, reflecting its broad role in metabolism. The gene's precise mapping helps in understanding its genetic context and potential interactions with neighbouring genes.
Protein structure
The 24-dehydrocholesterol reductase protein, encoded by the DHCR24 gene, consists of 516 amino acids. A key functional region within this protein is the FAD-binding PCMH-type domain, located between amino acids 58 and 234. This domain is crucial for binding flavin adenine dinucleotide (FAD), a coenzyme necessary for the enzyme's catalytic activity in reducing sterol molecules during cholesterol synthesis.
Key variants
Variants in the DHCR24 gene can alter the function of the 24-dehydrocholesterol reductase enzyme. These genetic changes can range from single base-pair substitutions to larger deletions or insertions, potentially affecting the enzyme's structure, stability, or catalytic efficiency. The impact of such variants can vary significantly, leading to a spectrum of biochemical and clinical outcomes related to cholesterol metabolism.
Sample of pathogenic variants
2 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.1218+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Non-immune hydrops fetalis |
c.307C>T | p.Arg103Cys | Pathogenic | - | Desmosterolosis |
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
Pathogenic variants within the DHCR24 gene are associated with desmosterolosis. This rare inherited condition is characterised by neurological problems, including developmental delay and brain abnormalities. Individuals with desmosterolosis may also exhibit elevated levels of desmosterol, an intermediate product in cholesterol synthesis, due to the impaired function of the DHCR24 enzyme. At least seven pathogenic variants in the DHCR24 gene have been identified in association with desmosterolosis.
No disease links recorded for this gene in our reference set.
UK clinical status
The DHCR24 gene is reviewed within the NHS Genomic Medicine Service, indicating its relevance in UK clinical genomics. It is listed as 'green' on several NHS England National Genomic Test Directory panels, including Arthrogryposis (R83), Foetal anomalies (R21), Hydrocephalus (R86), Intellectual disability, Likely inborn error of metabolism (R98), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders, as well as on the DDG2P list. This signifies that there is sufficient evidence to support its role in these conditions for diagnostic testing.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the DHCR24 gene?
The DHCR24 gene provides instructions for creating an enzyme called 24-dehydrocholesterol reductase. This enzyme is essential for the body's production of cholesterol, playing a key role in the final steps of converting precursor molecules into cholesterol.
Why is cholesterol important for the body?
Cholesterol is vital for numerous bodily functions. It is a critical component of cell membranes, insulates nerves (myelin), activates important developmental signalling pathways, and is a precursor for hormones and digestive acids.
What is desmosterolosis?
Desmosterolosis is a rare genetic condition caused by pathogenic variants in the DHCR24 gene. It is characterised by neurological issues such as brain abnormalities and developmental delay, resulting from the impaired conversion of desmosterol to cholesterol.
References
- Dias C, Rupps R, Millar B. Desmosterolosis: an illustration of diagnostic ambiguity of cholesterol synthesis disorders. Orphanet journal of rare diseases. 2014. PMID: 24961299
- Zerenturk EJ, Sharpe LJ, Ikonen E. Desmosterol and DHCR24: unexpected new directions for a terminal step in cholesterol synthesis. Progress in lipid research. 2013. PMID: 24095826
- Waterham HR, Koster J, Romeijn GJ. Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. American journal of human genetics. 2001. PMID: 11519011