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Genetic disorders coupled to ROS deficiency.

O'Neill S, Brault J, Stasia MJ, Knaus UG - Redox Biol (2015)

Bottom Line: Disturbances such as continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise, insufficient ROS production will be detrimental to health.More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease.A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure-function studies that will aid in predicting functional defects of clinical variants.

View Article: PubMed Central - PubMed

Affiliation: Conway Institute, University College Dublin, Dublin, Ireland.

No MeSH data available.


Related in: MedlinePlus

Molecular basis of chronic granulomatous disease. CGD is caused by alterations in CYBB, CYBA, NCF1, NCF2 or NCF4 encoding Nox2, p22phox, p47phox, p67phox and p40phox respectively. The main genetic form is X-linked CGD representing about 70% of total cases. Three autosomal recessive CGD forms, AR-CGD470, AR-CGD670, and AR-CGD220, represent the rest of the cases described, the AR-CGD470 being the most frequent form (25% of cases). Only one NCF4 variant has been described up to now.
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f0005: Molecular basis of chronic granulomatous disease. CGD is caused by alterations in CYBB, CYBA, NCF1, NCF2 or NCF4 encoding Nox2, p22phox, p47phox, p67phox and p40phox respectively. The main genetic form is X-linked CGD representing about 70% of total cases. Three autosomal recessive CGD forms, AR-CGD470, AR-CGD670, and AR-CGD220, represent the rest of the cases described, the AR-CGD470 being the most frequent form (25% of cases). Only one NCF4 variant has been described up to now.

Mentions: Understanding the composition of the multimeric phagocyte Nox2 oxidase was greatly aided by studies on neutrophils collected from CGD patients [7–9]. CGD is a genetically heterogeneous disease with all ethnic groups equally affected. The molecular basis of CGD is characterized by two types of transmission and four main genetic forms. The major genetic form of CGD is X-linked CGD caused by mutations in the CYBB gene (OMIM number 306400) encoding gp91phox (renamed Nox2) (Fig. 1). X-CGD represents about 70% of the total cases reported to date [10]. The other forms of CGD are autosomal recessive (AR), characterized by mutations in CYBA (OMIM number 233690), NCF1 (OMIM number 233700) and NCF2 (OMIM number 233710) encoding p22phox, p47phox and p67phox respectively [11]. Whereas AR-CGD220 and AR-CGD670 are extremely rare (less than 5% of cases), AR-CGD470 occurs with high frequency (about 25% of CGD cases) due to the presence of two NCF1 pseudogenes carrying the main mutation. Up to now only one case of AR-CGD in NCF4, encoding p40phox, was described [12]. Nox2 oxidase activity additionally requires activation of the small GTP-binding protein Rac, which was discovered concomitantly by Knaus et al. [13] and Abo et al. [14] in neutrophils. The importance of Rac2 was underlined by a case of severe immunodeficiency diverging from classical CGD in a 5-week-old child that was traced back to a dominant negative mutation in RAC2[15,16]. For CYBB, CYBA, NCF1 and NCF2 many variants harboring deletions, frame shifts, missense, nonsense and splice site mutations have been identified and are accessible at the immunodeficiency (ID) bases (http://structure.bmc.lu.se/idbase/).


Genetic disorders coupled to ROS deficiency.

O'Neill S, Brault J, Stasia MJ, Knaus UG - Redox Biol (2015)

Molecular basis of chronic granulomatous disease. CGD is caused by alterations in CYBB, CYBA, NCF1, NCF2 or NCF4 encoding Nox2, p22phox, p47phox, p67phox and p40phox respectively. The main genetic form is X-linked CGD representing about 70% of total cases. Three autosomal recessive CGD forms, AR-CGD470, AR-CGD670, and AR-CGD220, represent the rest of the cases described, the AR-CGD470 being the most frequent form (25% of cases). Only one NCF4 variant has been described up to now.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4550764&req=5

f0005: Molecular basis of chronic granulomatous disease. CGD is caused by alterations in CYBB, CYBA, NCF1, NCF2 or NCF4 encoding Nox2, p22phox, p47phox, p67phox and p40phox respectively. The main genetic form is X-linked CGD representing about 70% of total cases. Three autosomal recessive CGD forms, AR-CGD470, AR-CGD670, and AR-CGD220, represent the rest of the cases described, the AR-CGD470 being the most frequent form (25% of cases). Only one NCF4 variant has been described up to now.
Mentions: Understanding the composition of the multimeric phagocyte Nox2 oxidase was greatly aided by studies on neutrophils collected from CGD patients [7–9]. CGD is a genetically heterogeneous disease with all ethnic groups equally affected. The molecular basis of CGD is characterized by two types of transmission and four main genetic forms. The major genetic form of CGD is X-linked CGD caused by mutations in the CYBB gene (OMIM number 306400) encoding gp91phox (renamed Nox2) (Fig. 1). X-CGD represents about 70% of the total cases reported to date [10]. The other forms of CGD are autosomal recessive (AR), characterized by mutations in CYBA (OMIM number 233690), NCF1 (OMIM number 233700) and NCF2 (OMIM number 233710) encoding p22phox, p47phox and p67phox respectively [11]. Whereas AR-CGD220 and AR-CGD670 are extremely rare (less than 5% of cases), AR-CGD470 occurs with high frequency (about 25% of CGD cases) due to the presence of two NCF1 pseudogenes carrying the main mutation. Up to now only one case of AR-CGD in NCF4, encoding p40phox, was described [12]. Nox2 oxidase activity additionally requires activation of the small GTP-binding protein Rac, which was discovered concomitantly by Knaus et al. [13] and Abo et al. [14] in neutrophils. The importance of Rac2 was underlined by a case of severe immunodeficiency diverging from classical CGD in a 5-week-old child that was traced back to a dominant negative mutation in RAC2[15,16]. For CYBB, CYBA, NCF1 and NCF2 many variants harboring deletions, frame shifts, missense, nonsense and splice site mutations have been identified and are accessible at the immunodeficiency (ID) bases (http://structure.bmc.lu.se/idbase/).

Bottom Line: Disturbances such as continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise, insufficient ROS production will be detrimental to health.More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease.A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure-function studies that will aid in predicting functional defects of clinical variants.

View Article: PubMed Central - PubMed

Affiliation: Conway Institute, University College Dublin, Dublin, Ireland.

No MeSH data available.


Related in: MedlinePlus