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HSD17B4
hydroxysteroid 17-beta dehydrogenase 4
The HSD17B4 gene encodes the D-bifunctional protein, a peroxisomal enzyme crucial for the breakdown of certain fatty acids within cells. The HSD17B4 gene provides instructions for making the D-bifunctional protein, an enzyme located in peroxisomes.
HSD17B4 is located on the long (q) arm of chromosome 5, at band 5q23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The HSD17B4 gene, or hydroxysteroid 17-beta dehydrogenase 4, is responsible for producing the D-bifunctional protein. This protein functions as an enzyme, facilitating essential biochemical reactions within the cell.
Primarily located in peroxisomes, the D-bifunctional protein is involved in the breakdown of fatty acids, a critical metabolic process. Variants in the HSD17B4 gene can impact this function, leading to various inherited conditions.
What the gene does
The D-bifunctional protein, encoded by the HSD17B4 gene, is an enzyme that participates in two key biochemical reactions within peroxisomes. Peroxisomes are organelles containing enzymes that break down numerous substances, including certain fatty acids.
Specifically, the D-bifunctional protein is integral to the peroxisomal fatty acid beta-oxidation pathway. This pathway systematically shortens fatty acid molecules by two carbon atoms at a time. The D-bifunctional protein possesses two distinct regions with enzymatic activity: a hydratase domain and a dehydrogenase domain. These domains execute the second and third steps, respectively, of the beta-oxidation process, ultimately converting fatty acids into acetyl-CoA for cellular reuse.
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Chromosome location
The HSD17B4 gene is situated on chromosome 5, specifically at position 5q23.1. This location refers to the long arm (q) of chromosome 5, in region 2, band 3, sub-band 1. The gene's precise location on the chromosome helps in understanding its genetic context and potential interactions with other nearby genes.
Protein structure
The D-bifunctional protein produced from the HSD17B4 gene consists of 736 amino acids and features several distinct functional regions. It includes a (3R)-hydroxyacyl-CoA dehydrogenase region spanning amino acids 1-305. An Enoyl-CoA hydratase 2 region is located from amino acids 322-622, which encompasses a MaoC-like domain from amino acids 484-600. Additionally, a SCP2 domain is found towards the C-terminus, from amino acids 624-736, and a Microbody targeting signal motif is present at amino acids 734-736.
Key variants
Variants in the HSD17B4 gene can alter the function of the D-bifunctional protein, ranging from minor changes to complete loss of function. These genetic changes can affect either one or both of the protein's enzymatic activities. The impact of these variants on protein function can lead to a spectrum of health conditions.
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.1117del | p.Cys373fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
c.1168G>T | p.Gly390Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
c.1635dup | p.Gln546fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
c.1768-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
c.343del | p.Asp115fs | Pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
c.350A>T | p.Asp117Val | Pathogenic/Likely pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
c.627del | p.Val210fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
c.707T>A | p.Leu236Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.715-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
c.740T>A | p.Leu247Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Bifunctional peroxisomal enzyme deficiency |
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 in the HSD17B4 gene are associated with several inherited conditions, primarily affecting metabolic pathways and neurological function. These include D-bifunctional protein deficiency, a severe neurodegenerative disorder. Additionally, certain HSD17B4 variants are known to cause Perrault syndrome, characterised by hearing loss and ovarian abnormalities in affected individuals.
UK clinical status
The HSD17B4 gene is recognised within the NHS Genomic Medicine Service due to its clinical significance. It is listed as 'green' on multiple NHS England National Genomic Test Directory panels via PanelApp, indicating strong evidence for its gene-disease association. These panels include Monogenic hearing loss (R67), Early onset or syndromic epilepsy, Peroxisomal disorders, and Inherited white matter disorders, among others, highlighting its involvement in a range of complex conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the D-bifunctional protein?
The D-bifunctional protein is an enzyme encoded by the HSD17B4 gene. It is located in peroxisomes, where it plays a crucial role in breaking down certain fatty acids through a process called beta-oxidation.
What is D-bifunctional protein deficiency?
D-bifunctional protein deficiency is a severe inherited disorder caused by pathogenic variants in the HSD17B4 gene. It leads to the deterioration of nervous system functions, typically beginning in infancy.
How does HSD17B4 relate to Perrault syndrome?
Certain pathogenic variants in the HSD17B4 gene have been identified as a cause of Perrault syndrome. This condition is characterised by hearing loss in both males and females, and ovarian abnormalities in affected females.
References
- McMillan HJ, Worthylake T, Schwartzentruber J. Specific combination of compound heterozygous mutations in 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency. Orphanet journal of rare diseases. 2012. PMID: 23181892
- Pierce SB, Walsh T, Chisholm KM. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. American journal of human genetics. 2010. PMID: 20673864
- Ferdinandusse S, Denis S, Mooyer PA. Clinical and biochemical spectrum of D-bifunctional protein deficiency. Annals of neurology. 2006. PMID: 16278854
- Ferdinandusse S, Ylianttila MS, Gloerich J. Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis. American journal of human genetics. 2006. PMID: 16385454
- Möller G, van Grunsven EG, Wanders RJ. Molecular basis of D-bifunctional protein deficiency. Molecular and cellular endocrinology. 2001. PMID: 11165012