Dataset Information

Genetic disorders coupled to ROS deficiency.

ABSTRACT: Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. 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. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte Nox2 oxidase function due to genetic variants (CYBB, CYBA, NCF1, NCF2, NCF4) has been recognized as a direct cause of chronic granulomatous disease (CGD), an inherited immune disorder. 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.

SUBMITTER: O'Neill S

PROVIDER: S-EPMC4550764 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic disorders coupled to ROS deficiency.

O'Neill Sharon S Brault Julie J Stasia Marie-Jose MJ Knaus Ulla G UG

Redox biology 20150717

Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. 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. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte Nox2 oxidase ...[more]

PMID: 26210446

Similar Datasets

Project description:Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Project description:In neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD) and schizophrenia, impairment/malfunctioning of a subpopulation of interneurons expressing the calcium-binding protein parvalbumin (PV) -here termed Pvalb neurons- has gradually emerged as a possible cause. These neurons may represent a hub or point-of-convergence in the etiology of NDD. Increased oxidative stress associated with mitochondria impairment in Pvalb neurons is discussed as an essential step in schizophrenia etiology. Since PV downregulation is a common finding in ASD and schizophrenia individuals and PV-deficient (PV-/-) mice show a strong ASD-like behavior phenotype, we investigated the putative link between PV expression, alterations in mitochondria and oxidative stress. In a longitudinal study with 1, 3, and 6-months old PV-/- and wild type mice, oxidative stress was investigated in 9 Pvalb neuron subpopulations in the hippocampus, striatum, somatosensory cortex, medial prefrontal cortex, thalamic reticular nucleus (TRN) and cerebellum. In Pvalb neuron somata in the striatum and TRN, we additionally determined mitochondria volume and distribution at these three time points. In all Pvalb neuron subpopulations, we observed an age-dependent increase in oxidative stress and the increase strongly correlated with PV expression levels, but not with mitochondria density in these Pvalb neurons. Moreover, oxidative stress was elevated in Pvalb neurons of PV-/- mice and the magnitude of the effect was again correlated with PV expression levels in the corresponding wild type Pvalb neuron subpopulations. The PV-dependent effect was insignificant at 1 month and relative differences between WT and PV-/- Pvalb neurons were largest at 3 months. Besides the increase in mitochondria volume in PV's absence in TRN and striatal PV-/- Pvalb neurons fully present already at 1 month, we observed a redistribution of mitochondria from the perinuclear region toward the plasma membrane at all time points. We suggest that in absence of PV, slow Ca2+ buffering normally exerted by PV is compensated by a (mal)adaptive, mostly sub-plasmalemmal increase in mitochondria resulting in increased oxidative stress observed in 3- and 6-months old mice. Since PV-/- mice display core ASD-like symptoms already at 1 month, oxidative stress in Pvalb neurons is not a likely cause for their ASD-related behavior observed at this age.

Dataset Information

Genetic disorders coupled to ROS deficiency.

Publications

Genetic disorders coupled to ROS deficiency.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets