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Published on: September 16, 2022
A novel mutation in EROS (CYBC1) causes chronic granulomatous disease
Paige M Mortimer1, Esme Nichols1, Joe Thomas2
1Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, United Kingdom.
Insights
A novel mutation in the CYBC1 gene causes Chronic Granulomatous Disease (CGD), a rare immune disorder. This finding identifies a new genetic cause for CGD and suggests it may underlie other undiagnosed cases.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Chronic Granulomatous Disease (CGD) is an inherited immune deficiency characterized by recurrent infections and inflammation.
- It results from defective phagocyte NADPH oxidase, crucial for reactive oxygen species (ROS) production.
- A novel form, CGD5, linked to EROS (CYBC1) deficiency, has been identified, but its full nature remains unclear.
Purpose of the Study:
- To investigate the genetic basis of a novel form of CGD (CGD5).
- To identify the specific mutation in CYBC1 responsible for CGD5.
- To determine the prevalence and population distribution of the identified mutation.
Main Methods:
- Genetic sequencing to identify mutations in the CYBC1 gene.
- Analysis of patient samples to confirm the identified mutation.
- Population genetics analysis to determine allele frequency.
Main Results:
- A homozygous frameshift mutation in the CYBC1 gene was identified as the cause of CGD5.
- EROS (CYBC1) acts as a chaperone for gp91phox and influences other proteins like P2X7.
- Heterozygous carriers of this mutation are present in South Asian populations with a significant allele frequency.
Conclusions:
- The identified CYBC1 mutation is a significant cause of CGD.
- EROS deficiency leads to impaired ROS production and immune dysfunction.
- This finding expands the genetic landscape of CGD and suggests a potential cause for other undiagnosed cases.
Abstract:
Chronic Granulomatous Disease (CGD) is an inborn error of immunity characterised by opportunistic infection and sterile granulomatous inflammation. CGD is caused by a failure of reactive oxygen species (ROS) production by the phagocyte NADPH oxidase. Mutations in the genes encoding phagocyte NADPH oxidase subunits cause CGD. We and others have described a novel form of CGD (CGD5) secondary to lack of EROS (CYBC1), a highly selective chaperone for gp91phox. EROS-deficient cells express minimal levels of gp91phox and its binding partner p22phox, but EROS also controls the expression of other proteins such as P2X7. The full nature of CGD5 is currently unknown. We describe a homozygous frameshift mutation in CYBC1 leading to CGD. Individuals who are heterozygous for this mutation are found in South Asian populations (allele frequency = 0.00006545), thus it is not a private mutation. Therefore, it is likely to be the underlying cause of other cases of CGD.
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