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EBP
EBP cholestenol delta-isomerase
The EBP gene encodes an enzyme essential for cholesterol biosynthesis, playing a critical role in normal development and cellular function. The EBP gene provides instructions for creating 3β-hydroxysteroid-Δ8,Δ7-isomerase, an enzyme vital for cholesterol synthesis.
EBP is located on the short (p) arm of chromosome X, at band Xp11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
The EBP gene, or EBP cholestenol delta-isomerase, is responsible for producing an enzyme that plays a crucial role in the body's cholesterol synthesis pathway. Cholesterol is a waxy, fat-like substance fundamental for embryonic development and performs important functions throughout life. It is a key structural component of cell membranes and is involved in producing hormones and bile acids, which aid digestion.
Pathogenic variants in the EBP gene are associated with inherited conditions primarily affecting females, such as Conradi-Hünermann-Happle syndrome, which can present with abnormalities in bone, skin, and eyes. Understanding the EBP gene's function and associated conditions is important for genetic diagnostics and counselling.
What the gene does
The EBP gene provides instructions for synthesising the enzyme 3β-hydroxysteroid-Δ8,Δ7-isomerase. This enzyme is directly involved in a crucial stage of cholesterol production within the human body. Specifically, it facilitates the conversion of a molecule known as 8(9)-cholestenol into lathosterol. Lathosterol then undergoes further modifications by other enzymes to complete the synthesis of cholesterol.
Cholesterol is indispensable for various biological processes. It forms a vital structural component of cell membranes, contributing to their integrity and fluidity. Beyond its structural role, cholesterol is a precursor for the synthesis of steroid hormones, such as oestrogen and testosterone, and also for bile acids, which are critical for the digestion and absorption of fats. Given its multifaceted roles, the proper functioning of the EBP enzyme is essential for maintaining overall cellular and physiological health.
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Chromosome location
The EBP gene is located on the short (p) arm of the X chromosome at position 11.23, a region designated Xp11.23. The X chromosome is one of the two sex chromosomes, with females typically having two X chromosomes and males having one X and one Y chromosome. The precise location on the chromosome helps in mapping genetic variants and understanding their inheritance patterns. The EBP protein itself is composed of 230 amino acids.
Protein structure
The EBP protein, an enzyme central to cholesterol synthesis, consists of a specific functional region identified as the EXPERA domain. This domain spans amino acid residues 61 to 204 of the protein. The EXPERA domain is thought to be critical for the enzyme's isomerase activity, allowing it to catalyse the conversion of 8(9)-cholestenol to lathosterol within the cholesterol biosynthesis pathway. The precise three-dimensional structure and inter-domain interactions are key to its biological function.
Key variants
Variants in the EBP gene can alter the function of the 3β-hydroxysteroid-Δ8,Δ7-isomerase enzyme, disrupting the normal cholesterol synthesis pathway. These genetic changes can range from small deletions or insertions of genetic material to single building block changes within the gene. Such alterations can lead to a reduction or complete loss of enzyme activity, impacting the body's ability to produce essential cholesterol precursors. The clinical impact of a variant depends on its specific nature and location within the EBP gene.
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.182G>A | p.Trp61Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Chondrodysplasia punctata 2 X-linked dominant |
c.184C>T | p.Arg62Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Chondrodysplasia punctata 2 X-linked dominant |
c.204G>T | p.Trp68Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Chondrodysplasia punctata 2 X-linked dominant |
c.238G>A | p.Glu80Lys | Pathogenic/Likely pathogenic | ★★☆☆ | Connective tissue disorder |
c.261C>G | p.Tyr87Ter | Pathogenic | ★★☆☆ | Chondrodysplasia punctata 2 X-linked dominant |
c.293C>T | p.Ser98Phe | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.328C>T | p.Arg110Ter | Pathogenic | ★★☆☆ | Chondrodysplasia punctata 2 X-linked dominant |
c.329G>A | p.Arg110Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Chondrodysplasia punctata 2 X-linked dominant |
c.439C>T | p.Arg147Cys | Pathogenic/Likely pathogenic | ★★☆☆ | MEND syndrome |
c.440G>A | p.Arg147His | Pathogenic | ★★☆☆ | EBP-related disorders |
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 EBP gene are known to cause Conradi-Hünermann-Happle syndrome. This condition is inherited in an X-linked dominant pattern and predominantly affects females. It is characterised by a range of symptoms, including distinctive abnormalities of the bones, particularly punctate calcifications (stippling) in cartilage, as well as skin and eye anomalies. The severity and presentation of Conradi-Hünermann-Happle syndrome can vary among affected individuals.
Inheritance pattern
Conditions caused by pathogenic EBP variants typically follow x-linked dominant inheritance.
X-linked dominant: all daughters of an affected father inherit the altered X and are affected. Sons receive the father's Y and are unaffected.
UK clinical status
The EBP gene is recognised on several Gene Panels within the UK's NHS Genomic Medicine Service, reflecting its significance in diagnosing a range of inherited conditions. It is included on panels such as Arthrogryposis, Chondrodysplasia punctata, Clefting, Foetal anomalies (R21), Intellectual disability (R29), Limb disorders, Palmoplantar keratodermas (R166), Peroxisomal disorders, Skeletal dysplasia (R104), and Undiagnosed metabolic disorders. This widespread inclusion underscores the gene's relevance for diagnostic testing in the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Given the EBP gene's role in cholesterol synthesis, lifestyle choices that generally support metabolic health are broadly beneficial, though no specific lifestyle intervention can prevent or treat conditions directly caused by EBP gene variants. A balanced diet rich in fruits, vegetables, and whole grains, coupled with regular physical activity, supports overall cardiovascular and metabolic wellbeing. Maintaining a healthy weight and avoiding excessive consumption of saturated and trans fats are also generally recommended for cardiovascular health.
Supplement considerations
There is no conclusive scientific evidence to suggest that specific supplements can prevent or treat conditions caused by EBP gene variants. As the EBP gene is involved in a fundamental metabolic pathway, any intervention would need careful consideration. Individuals considering taking any supplements should always consult with a healthcare professional to ensure they are safe, appropriate, and do not interfere with any existing medical conditions or treatments.
Frequently asked questions
What is the primary function of the EBP gene?
The EBP gene provides instructions for an enzyme called 3β-hydroxysteroid-Δ8,Δ7-isomerase, which is vital for cholesterol biosynthesis. It converts 8(9)-cholestenol to lathosterol, a key step in producing cholesterol.
Which condition is primarily associated with EBP gene variants?
The EBP gene is primarily associated with Conradi-Hünermann-Happle syndrome, an X-linked dominant disorder characterised by skeletal, skin, and eye abnormalities, predominantly affecting females.
How is Conradi-Hünermann-Happle syndrome inherited?
Conradi-Hünermann-Happle syndrome follows an X-linked dominant inheritance pattern. This means a single altered copy of the EBP gene on the X chromosome is sufficient to cause the condition.
Is the EBP gene included in standard genetic testing panels in the UK?
Yes, the EBP gene is listed on several NHS Genomic Medicine Service Gene Panels in the UK, including those for Arthrogryposis, Chondrodysplasia punctata, and Skeletal dysplasia, reflecting its diagnostic importance.
What happens if the EBP enzyme does not function correctly?
If the EBP enzyme does not function correctly due to gene variants, it disrupts the normal cholesterol synthesis pathway. This can lead to the accumulation of abnormal cholesterol precursors and impact cellular structures and hormone production, contributing to conditions like Conradi-Hünermann-Happle syndrome.
References
- Furtado LV, Bayrak-Toydemir P, Hulinsky B. A novel X-linked multiple congenital anomaly syndrome associated with an EBP mutation. American journal of medical genetics. Part A. 2010. PMID: 20949533
- Ausavarat S, Tanpaiboon P, Tongkobpetch S. Two novel EBP mutations in Conradi-Hünermann-Happle syndrome. European journal of dermatology : EJD. 2008. PMID: 18573709
- Steijlen PM, van Geel M, Vreeburg M. Novel EBP gene mutations in Conradi-Hünermann-Happle syndrome. The British journal of dermatology. 2007. PMID: 17949453
- Milunsky JM, Maher TA, Metzenberg AB. Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X-linked dominant Conradi-Hunermann-Happle syndrome and a mutation in EBP. American journal of medical genetics. Part A. 2003. PMID: 12503101
- Herman GE, Kelley RI, Pureza V. Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome). Genetics in medicine : official journal of the American College of Medical Genetics. 2002. PMID: 12509714
- Ikegawa S, Ohashi H, Ogata T. Novel and recurrent EBP mutations in X-linked dominant chondrodysplasia punctata. American journal of medical genetics. 2000. PMID: 11038443
- Braverman N, Lin P, Moebius FF. Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome. Nature genetics. 1999. PMID: 10391219