Biology subjects

Smith, K. G.

Publications and source records attributed to Smith, K. G..

3 recordsLinked to original sources

bioRxiv2018

GRID - Genomics of Rare Immune Disorders: a highly sensitive and specific diagnostic gene panel for patients with primary immunodeficiencies

Primary Immune disorders affect 15,000 new patients every year in Europe. Genetic tests are usually performed on a single or very limited number of genes leaving the majority of patients without a genetic diagnosis. We designed, optimised and validated a new clinical diagnostic platform called GRID, Genomics of Rare Immune Disorders, to screen in parallel 279 genes, including 2015 IUIS genes, known to be causative of Primary Immune disorders (PID). Validation to clinical standard using more than 58,000 variants in 176 PID patients shows an excellent sensitivity, specificity. The customised and automated bioinformatics pipeline prioritises and reports pertinent Single Nucleotide Variants (SNVs), INsertions and DELetions (INDELs) as well as Copy Number Variants (CNVs). An example of the clinical utility of the GRID panel, is represented by a patient initially diagnosed with X-linked agammaglobulinemia due to a missense variant in the BTK gene with severe inflammatory bowel disease. GRID results identified two additional compound heterozygous variants in IL17RC, potentially driving the altered phenotype.

genomics↗

bioRxiv2018

EROS is required for phagocyte NADPH oxidase function in humans and its deficiency causes Chronic Granulomatous Disease.

The phagocyte respiratory burst is mediated by the phagocyte NADPH oxidase, a multi-protein subunit complex that facilitates production of reactive oxygen species and which is essential for host defence. Monogenic deficiency of individual subunits leads to chronic granulomatous disease (CGD), which is characterized by an inability to make reactive oxygen species, leading to severe opportunistic infections and auto-inflammation. However, not all cases of CGD are due to mutations in previously identified subunits. We recently showed that Eros, a novel and highly conserved ER-resident transmembrane protein, is essential for the phagocyte respiratory burst in mice because it is required for expression of gp91phox-p22phox heterodimer, which are the membrane bound components of the phagocyte NADPH oxidase. We now show that the function of EROS is conserved in human cells and describe a case of CGD secondary to a homozygous EROS mutation that abolishes EROS protein expression. This work demonstrates the fundamental importance of EROS in human immunity and describes a novel cause of CGD.\n\nClinical ImplicationsChronic granulomatous disease is caused by an inability to make reactive oxygen species via the phagocyte NADPH oxidase. Mutations in C17ORF62/EROS, which controls gp91phox- p22phox abundance, are a novel cause of chronic granulomatous disease.\n\nKey MessagesO_LIThe murine gene, Eros, is known to regulate abundance of gp91phox-p22phox heterodimer and Eros deficient mice are susceptible to infection\nC_LIO_LIWe show that the function of EROS is conserved in human cells and that a homozygous mutation in EROS causes chronic granulomatous disease\nC_LI

immunology↗

bioRxiv2017

Species abundance plays a dominant role in local and regional extinctions in freshwater communities and allows the identification of selective extinctions

Recent declines in global biodiversity emphasize that understanding the factors that determine extinction risk should be a priority for ecologists and conservation biologists. A key question is whether extinctions are nonrandom and selective, in which case knowledge of selectivity may help predict and prevent future extinction. We suggest, however, that a premature focus on the identification of selective, trait-based determinants of extinctions risk is problematic if the potential importance of stochastic extinction processes are not first considered. Within this context we aimed to determine the roles that stochastic extinction and species abundance play in extinction risk by applying a rarefaction-based null model approach to analyzing biodiversity declines and extinctions in an experimental system. We focused on aquatic macroinvertebrate declines and extinction caused by predation by fish (Lepomis cyanellus) in semi-natural freshwater mesocosms. We found that null-predicted local extirpations based on the random loss of individuals were a significant predictor of observed local extirpations, and that the majority of observed extinctions were consistent with stochastic mechanisms of extinction, as predicted by a rarefaction model. We were able to identify a number of selective extinctions that were not predicted by the rarefaction model, and while these were relatively rare, they contributed to greater-than-expected loss of diversity at both local (mesocosm) and regional (whole experiment) spatial scales. Our results confirm that species abundance and occupancy are among the most important factors in identifying extinction risk in response to a disturbance. Moreover, owing to our use of a stochastic null model, we also conclude that measures of abundance are important indicators of extinction probability because they are operated on by the random loss of individuals, suggesting that stochastic extinction is an important process in this system and in biodiversity loss in general.

ecology↗