ORCID Profile
0000-0003-2840-4851
Current Organisation
Garvan Institute of Medical Research
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Publisher: American Society for Clinical Investigation
Date: 06-11-2017
DOI: 10.1172/JCI95545
Publisher: Springer Science and Business Media LLC
Date: 15-02-2018
DOI: 10.1038/S41598-018-20435-9
Abstract: Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis s le size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1 , LINC02052 and CRYGS , LMX1B , and LMO7 using single variant tests, one additional locus ( C9 ) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2018
DOI: 10.1038/S41588-018-0176-Y
Abstract: Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide
Publisher: Springer Science and Business Media LLC
Date: 18-09-2019
DOI: 10.1038/S41590-019-0492-0
Abstract: Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.
Publisher: BMJ
Date: 29-03-2022
DOI: 10.1136/BJOPHTHALMOL-2020-317461
Abstract: Recent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry. The authors completed a case–control cross-sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly s led from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of /22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores. A total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108). This study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.
Publisher: Cold Spring Harbor Laboratory
Date: 05-11-2020
DOI: 10.1101/2020.11.03.367623
Abstract: Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time-intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach we perform a systematic comparison of the distribution of VCDR and VDD, and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI based gradings increased estimates of heritability by ~50% for VCDR and VDD. Our GWAS identified more than 200 loci for both VCDR and VDD (double the number of loci from previous studies), uncovers dozens of novel biological pathways, with many of the novel loci also conferring risk for glaucoma.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
Publisher: Cold Spring Harbor Laboratory
Date: 20-03-2022
DOI: 10.1101/2022.03.19.485004
Abstract: Monogenic diseases can often manifest erse clinical phenotypes and cause diagnostic dilemmas. While monoallelic loss-of-function variants in TNFAIP3 (Haploinsufficiency of A20 HA20) cause a highly penetrant autoinflammatory disease, the variable expressivity suggest a role for additional genetic and environmental disease modifiers. Here, we identify critically ill children who inherited a family-specific TNFAIP3 deletion from one of their otherwise healthy parents. Each of the probands also inherited in trans a subtle loss-of-function I207L TNFAIP3 variant that is common in Oceania, originally introgressed from Denisovans. Modelling this compound heterozgous state in mice under specific pathogen free conditions demonstrated a reduced threshold to break immune tolerance. Exaggerated immune responses were precipitated by inheriting the two genetic hits on the TNFAIP3 checkpoint coupled with increasing the microbial challenge to immune tolerance, either by co-housing with pet store mice carrying a wild microbial burden or by transient dietary exposure to a chemical that diminishes the intestinal mucin barrier separating gut microbes from immune sensing systems. These data illuminate second-hit genetic and environmental modifiers contributing to complex inflammatory and autoimmune disease. Increased mechanistic understanding of the presence and contribution of disease modifiers will aid diagnostic and prognostic patient stratification and potentially reveal novel therapeutic opportunities.
Publisher: American Society of Hematology
Date: 14-06-2012
DOI: 10.1182/BLOOD-2012-03-417949
Abstract: TNFα is a powerful inflammatory stimulus, central both to the control of infection, and as an agent of inflammatory disease. The most potent inducers of TNFα secretion signal through the Toll-like receptors, and we describe here a chemically-induced mutation that impairs this response in macrophages. A missense mutation was revealed in the gene encoding the inactive rhomboid protease iRhom2, which was not complemented by a null allele of the same gene. Neither the missense nor the null allele affected TLR-induced secretion of IL-6. Moreover, unlike a mutation in TNFα, the iRhom2 missense mutation did not cause enhanced susceptibility to colitis induced by dextran sodium sulfate. These results establish a specific role for iRhom2 in the secretion of TNFα, and present a new target for the modulation of inflammation.
Publisher: The American Association of Immunologists
Date: 04-2011
Abstract: TLR7 is the mammalian receptor for ssRNA and some nucleotide-like small molecules. We have generated a mouse by N-nitrose-N′-ethyl urea mutagenesis in which threonine 68 of TLR7 was substituted with isoleucine. Cells bearing this mutant TLR7 lost the sensitivity to the small-molecule TLR7 agonist resiquimod, hence the name TLR7rsq1. In this work, we report the characterization of this mutant protein. Similar to the wild-type counterpart, TLR7rsq1 localizes to the endoplasmic reticulum and is expressed at normal levels in both primary cells and reconstituted 293T cells. In addition to small-molecule TLR7 agonists, TLR7rsq1 fails to be activated by ssRNA. Whole-transcriptome analysis demonstrates that TLR7 is the exclusive and indispensable receptor for both classes of ligands, consistent with the fact that both ligands induce highly similar transcriptional signatures in TLR7wt/wt splenocytes. Thus, TLR7rsq1 is a bona fide phenocopy of the TLR7 null mouse. Because TLR7rsq1 binds to ssRNA, our studies imply that the N-terminal portion of TLR7 triggers a yet to be identified event on TLR7. TLR7rsq1 mice might represent a valuable tool to help elucidate novel aspects of TLR7 biology.
Publisher: Elsevier BV
Date: 12-2007
Publisher: Cold Spring Harbor Laboratory
Date: 22-10-2021
DOI: 10.1101/2021.10.19.21264544
Abstract: Integrating polygenic risk scores (PRS) into healthcare has the potential to stratify an in idual’s risk of glaucoma across a broad population. Glaucoma is the most common cause of irreversible blindness worldwide, therefore effective screening for glaucoma endorsed by the population is highly important. This study assessed the attitude of unaffected in iduals towards PRS testing for glaucoma, and sought to identify factors associated with interest in testing. We surveyed 418 unaffected in iduals including those with a first-degree relative with glaucoma (n=193), those who had a recent eye examination (n=117), and general members of the community (n=108). Overall, 71.3% indicated an interest in taking a polygenic risk test for glaucoma. Interest was more likely in those who believed glaucoma to be a severe medical condition (OR 14.58, 95%CI (1.15-185.50), p=0.039), those concerned about developing glaucoma (OR 4.37, 95%CI (2.32-8.25), p .001), those with an intention to take appropriate measures regarding eye health (OR 2.39, 95%CI (1.16-4.95), p=0.019), and those preferring to know if considered to be at-risk or not (OR 4.52, 95%CI (2.32-8.83), p .001). These findings represent a valuable assessment of general public interest in glaucoma polygenic risk testing, which will be integral to the implementation and uptake of novel PRS based tests into clinical practice.
Publisher: Hindawi Limited
Date: 11-05-2021
DOI: 10.1002/HUMU.24214
Abstract: Gelsolin (GSN) variants have been implicated in amyloidosis of the Finnish type. This case series reports a novel GSN:c.1477T>C,p.(Trp493Arg) variant in a family with ocular and systemic features consistent with Finnish Amyloidosis. Exome sequencing performed on affected in iduals from two families manifesting cutis laxa and polymorphic corneal stromal opacities demonstrated the classic GSN:c.654G>A,p.Asp214Asn variant in single affected in idual from one family, and a previously undocumented GSN:c.1477T>C variant in three affected first-degree relatives from a separate family. Immunohistochemical studies on corneal tissue from a proband with the c.1477T>C variant identified gelsolin protein within histologically defined corneal amyloid deposits. This study reports a novel association between the predicted pathogenic GSN:c.1477T>C variant and amyloidosis of the Finnish type, and is the first to provide functional evidence of a pathological GSN variant at a locus distant to the critical G2 calcium-binding region, resulting in the phenotype of amyloidosis of the Finnish type.
Publisher: American Society of Neuroradiology (ASNR)
Date: 07-09-2023
DOI: 10.3174/AJNR.A7995
Publisher: American Society for Clinical Investigation
Date: 12-2022
DOI: 10.1172/JCI156967
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
Publisher: Wiley
Date: 11-03-2014
DOI: 10.1111/IMM.12220
Publisher: American Medical Association (AMA)
Date: 07-2015
DOI: 10.1001/JAMAOPHTHALMOL.2015.0980
Abstract: Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty in iduals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. Identification and characterization of CYP1B1 sequence variants. We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%] P = .02 odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%] P = .02 odds ratio, 2.0 [95% CI, 0.3-0.9]). In iduals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB F1,126 = 5.90 P = .02 partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years F1,122 = 7.18 P = .008 ηp2 = 0.06) than patients without CYP1B1 pathogenic variants. Patients with advanced JOAG based on visual field loss had enrichment of CYP1B1 pathogenic variants and a more severe phenotype compared with unaffected controls and patients with nonadvanced JOAG.
Publisher: Proceedings of the National Academy of Sciences
Date: 25-04-2011
Abstract: Transporters at the hepatic canalicular membrane are essential for the formation of bile and the prevention of cholestatic liver disease. One such ex le is ATP8B1, a P4-type ATPase disrupted in three inherited forms of intrahepatic cholestasis. Mutation of the X-linked mouse gene Atp11c , which encodes a paralogous P4-type ATPase, precludes B-cell development in the adult bone marrow, but also causes hyperbilirubinemia. Here we explore this hyperbilirubinemia in two independent Atp11c mutant mouse lines, and find that it originates from an effect on nonhematopoietic cells. Liver function tests and histology revealed only minor pathology, although cholic acid was elevated in the serum of mutant mice, and became toxic to mutant mice when given as a dietary supplement. The majority of homozygous mutant females also died of dystocia in a maternal genotype-specific manner. ATP11C therefore represents a multifunctional transporter, essential for adult B-cell development, the prevention of intrahepatic cholestasis, and parturition, and is a new candidate for genetically undiagnosed cases of cholestasis and dystocia in humans.
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2018
DOI: 10.1101/297077
Abstract: Congenital glaucoma is a significant cause of irreversible blindness. In some instances glaucoma is associated with developmental abnormalities of the ocular anterior segment, which can impair drainage of aqueous humor, leading to an increase in intraocular pressure. Genome sequencing was performed on a parent-proband congenital glaucoma trio, with exome sequencing of 79 additional in iduals with suspected primary congenital glaucoma. We describe a unique ocular anterior segment dysgenesis associated with congenital glaucoma in four in iduals from three unrelated families. In each case, disease was associated with compound heterozygous variants in CPAMD8 , a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation of key drainage structures and the development of high intraocular pressure and glaucoma. This study reveals a unique genetic cause of childhood glaucoma, and expands the phenotypic spectrum of CPAMD8 -associated ocular disease.
Publisher: Wiley
Date: 24-11-2021
DOI: 10.1002/AJMG.A.61982
Abstract: Axenfeld‐Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld‐Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. In iduals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio‐Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty‐four in iduals from 18 families were included. FOXC1 variants were present in 64.7% of in iduals and PITX2 variants in 35.3% of in iduals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low‐set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in in iduals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.
Publisher: Rockefeller University Press
Date: 03-08-2009
Abstract: Proteins of the Bcl-2 family are critical regulators of apoptosis, but how its BH3-only members activate the essential effectors Bax and Bak remains controversial. The indirect activation model suggests that they simply must neutralize all of the prosurvival Bcl-2 family members, whereas the direct activation model proposes that Bim and Bid must activate Bax and Bak directly. As numerous in vitro studies have not resolved this issue, we have investigated Bim's activity in vivo by a genetic approach. Because the BH3 domain determines binding specificity for Bcl-2 relatives, we generated mice having the Bim BH3 domain replaced by that of Bad, Noxa, or Puma. The mutants bound the expected subsets of prosurvival relatives but lost interaction with Bax. Analysis of the mice showed that Bim's proapoptotic activity is not solely caused by its ability to engage its prosurvival relatives or solely to its binding to Bax. Thus, initiation of apoptosis in vivo appears to require features of both models.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-08-2012
Abstract: Copper influences the pathogenesis of prion disease, but whether it is beneficial or detrimental remains controversial. Copper homeostasis is also essential for normal physiology, as highlighted by the spectrum of diseases caused by disruption of the copper transporting enzymes ATP7A and ATP7B. Here, by using a forward genetics approach in mice, we describe the isolation of three alleles of Atp7a , each with different phenotypic consequences. The mildest of the three, Atp7a brown , was insufficient to cause lethality in hemizygotes or mottling of the coat in heterozygotes, but did lead to coat hypopigmentation and reduced copper content in the brains of hemizygous males. When challenged with Rocky Mountain Laboratory scrapie, the onset of prion disease was delayed in Atp7a brown mice, and significantly less proteinase-resistant prion protein was found in the brains of moribund Atp7a brown mice compared with WT littermates. Our results establish that ATP7A-mediated copper homeostasis is important for the formation of pathogenic proteinase-resistant prion protein.
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-05-2021
DOI: 10.1167/TVST.10.6.14
Publisher: Springer Science and Business Media LLC
Date: 20-03-2011
DOI: 10.1038/NI.2012
Publisher: Proceedings of the National Academy of Sciences
Date: 03-07-2012
Abstract: Using chemical germ-line mutagenesis, we screened mice for defects in the humoral immune response to a type II T-independent immunogen and an experimental alphavirus vector. A total of 26 mutations that impair humoral immunity were recovered, and 19 of these mutations have been positionally cloned. Among the phenovariants were bumble , cellophane , and Worker ascribed to mutations in Nfkbid , Zeb1 , and Ruvbl2 , respectively. We show that IκBNS, the nuclear IκB-like protein encoded by Nfkbid , is required for the development of marginal zone and peritoneal B-1 B cells and additionally required for extrafollicular antibody responses to T-independent and -dependent immunogens. Zeb1 is also required for marginal zone and peritoneal B-1 B-cell development as well as T-cell development, germinal center formation, and memory B-cell responses. Finally, Ruvbl2 is required for T-cell development and maximal T-dependent antibody responses. Collectively, the mutations that we identified give us insight into the points at which disruption of an antibody response can occur. All of the mutations identified to date directly affect lymphocyte development or function none have an exclusive effect on cells of the innate immune system.
Publisher: Elsevier BV
Date: 2015
Publisher: Elsevier BV
Date: 12-2021
Publisher: The Company of Biologists
Date: 13-11-2014
Abstract: iRhoms are closely related to rhomboid intramembrane proteases but lack catalytic activity. In mammals iRhoms are known to regulate the trafficking of TACE, the protease that cleaves the membrane bound inflammatory cytokine TNF. We have mapped a spontaneously occurring mouse mutation with a loss of hair phenotype, curly bare (cub), to the Rhbdf2 locus, which encodes the iRhom2 protein. The cub deletion removes the first 268 amino acids of the iRhom2 protein but is not a loss of function. We have also identified a previously reported suppressor of cub, called Mcub (modifier of curly bare), and find it to be a loss of function allele of the hiregulin gene (Areg). Amphiregulin is an activating ligand of the epidermal growth factor receptor (EGFR) that, like TNF, is released by TACE. Our results therefore imply a regulatory link between iRhoms and EGFR signalling in mammals. We have tested the model that the cub mutation leads to iRhom2 hyperactivity and consequently excess TACE processing of hiregulin and elevated EGFR signalling. Our results do not support this hypothesis: we find that, compared to wild-type cells, cub mutant embryonic fibroblasts release less hiregulin, and that the cub mutant form of iRhom2 is less able than wild type to bind to TACE and promote its maturation.
Publisher: Proceedings of the National Academy of Sciences
Date: 14-06-2016
Abstract: Cellular metabolism is tightly regulated by AMP-activated protein kinase (AMPK): the function of which is influenced by folliculin (FLCN), folliculin-interacting protein (FNIP)1, and FNIP2. FLCN is a known tumor-suppressor protein that is mutated in Birt–Hogg–Dubé syndrome, whereas FNIP1 and FNIP2 are binding partners of FLCN. Previous reports have suggested that the FLCN/FNIP1/FNIP2 complex acts a positive regulator of AMPK, whereas other reports suggest the opposite. Using a new mouse model of FNIP1 deficiency, our findings support the latter: we found that mutation of Fnip1 leads to B-cell deficiency and the development of a cardiomyopathy similar to mice and humans with gain-of-function mutations in AMPK.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2010
DOI: 10.1038/NI.1847
Publisher: American Society for Microbiology
Date: 02-2012
DOI: 10.1128/JVI.05660-11
Abstract: The downregulation of translation through eIF2α phosphorylation is a cellular response to erse stresses, including viral infection, and is mediated by the GCN2 kinase, protein kinase R (PKR), protein kinase-like endoplasmic reticulum kinase (PERK), and heme-regulated inhibitor kinase (HRI). Although PKR plays a major role in defense against viruses, other eIF2α kinases also may respond to viral infection and contribute to the shutdown of protein synthesis. Here we describe the recessive, loss-of-function mutation atchoum ( atc ) in Eif2ak4 , encoding GCN2, which increased susceptibility to infection by the double-stranded DNA viruses mouse cytomegalovirus (MCMV) and human adenovirus. This mutation was identified by screening macrophages isolated from mice carrying N -ethyl- N -nitrosourea (ENU)-induced mutations. Cells from Eif2ak4 atc/atc mice failed to phosphorylate eIF2α in response to MCMV. Importantly, homozygous Eif2ak4 atc mice showed a modest increase in susceptibility to MCMV infection, demonstrating that translational arrest dependent on GCN2 contributes to the antiviral response in vivo .
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 10-03-2017
Abstract: Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of in iduals with advanced early-onset POAG. The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninety-three previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31×10-16). Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.
Publisher: Springer Science and Business Media LLC
Date: 07-2008
DOI: 10.1038/NRI2336
Abstract: Partial T-cell immunodeficiencies constitute a heterogeneous cluster of disorders characterized by an incomplete reduction in T-cell number or activity. The immune deficiency component of these diseases is less severe than that of the severe T-cell immunodeficiencies and therefore some ability to respond to infectious organisms is retained. Unlike severe T-cell immunodeficiencies, however, partial immunodeficiencies are commonly associated with hyper-immune dysregulation, including autoimmunity, inflammatory diseases and elevated IgE production. This causative association is counter-intuitive--immune deficiencies are caused by loss-of-function changes to the T-cell component, whereas the coincident autoimmune symptoms are the consequence of gain-of-function changes. This Review details the genetic basis of partial T -cell immunodeficiencies and draws on recent advances in mouse models to propose mechanisms by which a reduction in T-cell numbers or function may disturb the population-dependent balance between activation and tolerance.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-10-2015
Abstract: Chaperones in the endoplasmic reticulum (ER) are essential for protein folding and for the maintenance of an efficient secretory pathway. These chaperones can also accompany their substrates during transit from the ER to the Golgi. The prototypical mammalian KDEL receptor (KDELR1) functions by returning chaperones and other proteins to the ER. We show that a recessive missense mutation of Kdelr1 in mice is associated with low numbers of lymphocytes in the blood (lymphopenia), reduced expression of the T-cell receptor, and compromised antiviral immunity.
Publisher: The American Association of Immunologists
Date: 15-06-2014
Abstract: TLRs 7 and 8 are pattern recognition receptors controlling antiviral host defense or autoimmune diseases. Apart from foreign and host RNA, synthetic RNA oligoribonucleotides (ORN) or small molecules of the imidazoquinoline family activate TLR7 and 8 and are being developed as therapeutic agonists. The structure-function relationships for RNA ORN and imidazoquinoline sensing and consequent downstream signaling by human TLR7 and TLR8 are unknown. Proteome- and genome-wide analyses in primary human monocyte-derived dendritic cells here showed that TLR8 sensing of RNA ORN versus imidazoquinoline translates to ligand-specific differential phosphorylation and transcriptional events. In addition, TLR7 and 8 ectodomains were found to discriminate between RNA ORN and imidazoquinolines by overlapping and nonoverlapping recognition sites to which murine loss-of-function mutations and human naturally occurring hyporesponsive polymorphisms map. Our data suggest TLR7 and TLR8 can signal in two different “modes” depending on the class of ligand. Considering RNA ORN and imidazoquinolines have been regarded as functionally interchangeable, our study highlights important functional incongruities whose understanding will be important for developing TLR7 or 8 therapeutics with desirable effector and safety profiles for in vivo application.
Publisher: Rockefeller University Press
Date: 26-12-2012
DOI: 10.1084/JEM.20112084
Abstract: In this study, we describe a chemically induced mouse mutation that caused a complete and cell-intrinsic T cell deficiency. Development of other lymphoid lineages was also partially impaired and was severely compromised under competitive conditions. Positional cloning, retroviral transduction, and a somatic reversion event revealed that the causative mutation lay within Zbtb1 (zinc finger and BTB domain containing 1), a gene conserved throughout vertebrate evolution. Our data establish ZBTB1 as a critical determinant of T cell development and lymphopoiesis in general, most likely by acting as a transcriptional regulator.
Publisher: Wiley
Date: 20-03-2007
Abstract: Genetic variants of interleukin 2 (IL-2) and its receptor are associated with murine and human susceptibility to Type 1 diabetes, yet the role of IL-2 in controlling pancreatic islet-reactive T cells is unknown. Here, we develop a model where IL-2 deficiency precipitates a breakdown of self-tolerance and progression to diabetes, and its action upon diabetogenic islet-specific CD4 T cells can be tracked. We find that IL-2 is not required for Aire-dependent thymic clonal deletion of high-avidity diabetogenic clones, but is essential for thymic formation of islet-specific Foxp3-expressing CD4 T cells. The absence of IL-2 results in the expansion of low-avidity Foxp3(-) islet-reactive CD4 T cells. The mechanism by which IL-2 prevents diabetes is therefore through the establishment of a repertoire of islet-reactive Foxp3(+) T cells within the thymus, and limitation of the peripheral activation of low-avidity islet-reactive T cells that normally escape thymic negative selection.
Publisher: Frontiers Media SA
Date: 23-07-2019
Publisher: Wiley
Date: 03-10-2016
DOI: 10.1002/MGG3.248
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Date: 07-10-2020
DOI: 10.1167/IOVS.61.12.6
Publisher: Elsevier BV
Date: 07-2021
Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2019
DOI: 10.1101/589507
Abstract: Resisting or tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here, genomic analyses of anatomically modern humans, extinct Denisovan hominins, and mice revealed a series of missense variants in the immune response inhibitor A20 (encoded by TNFAIP3 ), substituting non-catalytic residues of the ubiquitin protease domain to diminish IκB-dependent phosphorylation and activation of A20. Two A20 variants with partial phosphorylation deficits appeared beneficial: one originating in Denisovans and introgressed in modern humans throughout Oceania, and another in a mouse strain resistant to Coxsackievirus. By contrast, a variant with 95% loss of phosphorylation caused spontaneous inflammatory disease in humans and mice. Analysis of the partial phosphorylation variant in mice revealed diminished tolerance of bacterial lipopolysaccharide or to poxvirus inoculation as trade-offs for enhanced immunity. Modern and ancient variants reveal a genetically tunable element for balancing immunity and microbial tolerance.
Publisher: American Medical Association (AMA)
Date: 09-2021
Publisher: Informa UK Limited
Date: 02-01-2019
DOI: 10.1080/13816810.2018.1561904
Abstract: Stability of the crystalline lens requires formation of microfibril bundles and their higher-order structures of ciliary zonules. Trauma, malformation, or degeneration of the ciliary zonules can lead to dislocation or displacement of the lens, which in turn can cause transient or permanent loss of visual acuity. The purpose of this study was to identify the predicted substrates of aspartyl/asparaginyl hydroxylase (ASPH), a 2-oxoglutarate- and Fe A single proband of European ancestry with spherophakia and high myopia was subjected to exome sequencing. Proteins containing the ASPH hydroxylation motif were identified within the SwissProt protein database. We identified 105 putative substrates of ASPH-mediated hydroxylation in the human proteome, of which two (fibrillin-1 and latent transforming growth factor beta binding protein-2) are associated with inherited ectopia lentis syndromes, and are essential for microfibril and ciliary zonule development. Our results implicate ASPH-mediated hydroxylation in the formation of FBN1/LTBP2 microfibril bundles and competent ciliary zonules.
Publisher: Cold Spring Harbor Laboratory
Date: 03-02-2020
DOI: 10.1101/2020.01.30.927822
Abstract: We conducted a large multi-ethnic meta-analysis of genome-wide association studies for primary open-angle glaucoma (POAG) on a total of 34,179 cases vs 349,321 controls, and identified 127 independent risk loci, almost doubling the number of known loci for POAG. The majority of loci have broadly consistent effect across European, Asian and African ancestries. We identify a link, both genome-wide and at specific loci, between POAG and Alzheimer’s disease. Gene expression data and bioinformatic functional analyses provide further support for the functional relevance of the POAG risk genes. Several drug compounds target these risk genes and may be potential candidates for developing novel POAG treatments.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2012
Abstract: We present a compendium of N -ethyl- N -nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer-reviewed publications 2) to assess the characteristics of these mutations and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype. In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied. Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions, and may lead to refined predictions as to whether specific amino acid changes are responsible for observed phenotypes. These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice.
Publisher: Cold Spring Harbor Laboratory
Date: 04-12-2019
DOI: 10.1101/19013599
Abstract: Refractive error is caused by a disparity between the axial length and focusing power of the eye. Nanophthalmos is a rare ocular abnormality in which both eyes are abnormally small, typically causing extreme hyperopic refractive error, and associated with an increased risk of angle-closure glaucoma. A cohort of 40 in iduals from 13 unrelated nanophthalmos kindreds were recruited, with 11 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in PRSS56 (4), MFRP (3), and previously reported variants in TMEM98 (1) and MYRF (1). Two of the four PRSS56 probands harboured the previously described c.1066dupC frameshift variant implicated in over half of all reported PRSS56 kindreds, with surrounding haplotypes distinct from each other, and from a previously reported Tunisian c.1066dupC haplotype. In iduals with a genetic diagnosis had shorter mean axial lengths ( P =7.22×10 −9 ) and more extreme hyperopia ( P =0.0005) than those without a genetic diagnosis, with recessive forms associated with the shortest axial lengths and highest hyperopia. All in iduals with an axial length below 18 mm in their smaller eye (17/17) were assigned a genetic diagnosis. These findings detail the genetic architecture of nanophthalmos in an Australian cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/EJHG.2017.59
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 07-2020
Publisher: The American Association of Immunologists
Date: 15-03-2015
Abstract: Gene variants that disrupt TCR signaling can cause severe immune deficiency, yet less disruptive variants are sometimes associated with immune pathology. Null mutations of the gene encoding the scaffold protein Src homology 2 domain–containing leukocyte protein of 76 kDa (SLP-76), for ex le, cause an arrest of T cell positive selection, whereas a synthetic membrane-targeted allele allows limited positive selection but is associated with proinflammatory cytokine production and autoantibodies. Whether these and other enigmatic outcomes are due to a biochemical uncoupling of tolerogenic signaling, or simply a quantitative reduction of protein activity, remains to be determined. In this study we describe a splice variant of Lcp2 that reduced the amount of wild-type SLP-76 protein by ∼90%, disrupting immunogenic and tolerogenic pathways to different degrees. Mutant mice produced excessive amounts of proinflammatory cytokines, autoantibodies, and IgE, revealing that simple quantitative reductions of SLP-76 were sufficient to trigger immune dysregulation. This allele reveals a dose-sensitive threshold for SLP-76 in the balance of immunity and immune dysregulation, a common disturbance of atypical clinical immune deficiencies.
Publisher: Wiley
Date: 11-02-2014
DOI: 10.1038/ICB.2014.8
Publisher: Informa UK Limited
Date: 27-05-2022
DOI: 10.1080/09273948.2022.2074464
Abstract: Orbital myositis is a rare sporadic eye disease associated with extraocular eye muscle inflammation. To date, there have been two reports of familial orbital myositis (FOM), which demonstrate partially penetrant autosomal dominant inheritance. We report six new Australian cases of FOM, four of whom extend one of the reported pedigrees, as well as a separate mother and daughter manifesting orbital myositis, which constitutes a third report of familial occurrence. We can confirm that the disease has onset in childhood, appearing to go into remission in adult life, and that the inflammation is corticosteroid-responsive. However, one patient went on to develop permanent diplopia in upgaze. We also report two children suffering chronic pain and diplopia who demonstrated complete resolution of symptoms with the anti-TNF-α monoclonal infliximab. Uncontrolled FOM in childhood may result in permanent extraocular eye muscle damage, while TNF-α blockade provides an excellent steroid-sparing effect.
Publisher: Portland Press Ltd.
Date: 29-09-2020
DOI: 10.1042/BIO20200063
Abstract: Glaucoma is the leading cause of irreversible blindness globally and is one of the most heritable human diseases. Labelled the ‘silent thief of sight’, primary open angle glaucoma is a progressive neurodegenerative disease of the retinal ganglion cells that can be treated by reducing intraocular pressure. Treatment is highly effective in preventing glaucoma vision loss however, as it is asymptomatic in its early stages, many in iduals with glaucoma are diagnosed only after a considerable amount of vision has already been lost. Given the high heritability of glaucoma, genetic risk profiling is now being explored as a way to identify in iduals at the highest risk of developing glaucoma and those who will require the most intense treatment. Combining rare glaucoma-causing variants in single genes with more common genetic risk variants across many genes means that clinicians may soon be able to effectively stratify glaucoma risk across whole populations. This promises to maximize the efficiency of healthcare spending by prioritizing surveillance of high-risk in iduals and reducing irreversible vision loss through early commencement of vision-saving treatments.
Publisher: Cold Spring Harbor Laboratory
Date: 02-02-2023
DOI: 10.1101/2023.02.01.526555
Abstract: The exact pathogenesis of primary open-angle glaucoma (POAG) is poorly understood. Genome-wide association studies (GWAS) have recently uncovered many loci associated with variation in intraocular pressure (IOP) a crucial risk factor for POAG. Artificial intelligence (AI) can be used to interrogate the effect of specific genetic knockouts on the morphology of trabecular meshwork cells (TMCs), the regulatory cells of IOP. Sixty-two genes at fifty-five loci associated with IOP variation were knocked out in primary TMC lines. All cells underwent high-throughput microscopy imaging after being stained with a five-channel fluorescent cell staining protocol. A convolutional neural network (CNN) was trained to distinguish between gene knockout and normal control cell images. The area under the receiver operator curve (AUC) metric was used to quantify morphological variation in gene knockouts to identify potential pathological perturbations. Cells where RALGPS1 had been perturbed demonstrated the greatest morphological variation from normal TMCs (AUC 0.851, SD 0.030), followed by LTBP2 (AUC 0.846, SD 0.029) and BCAS3 (AUC 0.845, SD 0.020). Of seven multi-gene loci, five had statistically significant differences in AUC (p .05) between genes, allowing for pathological gene prioritisation. The mitochondrial channel most frequently showed the greatest degree of morphological variation (33.9% of cell lines). We demonstrate a robust method for functionally interrogating genome-wide association signals using high-throughput microscopy and AI. Genetic variations inducing marked morphological variation can be readily identified, allowing for the gene-based dissection of loci associated with complex traits.
Publisher: Springer Science and Business Media LLC
Date: 30-01-2018
DOI: 10.1038/S41467-017-02806-4
Abstract: Computational inference of mutation effects is necessary for genetic studies in which many mutations must be considered as etiologic candidates. Programs such as PolyPhen-2 predict the relative severity of damage caused by missense mutations, but not the actual probability that a mutation will reduce/eliminate protein function. Based on genotype and phenotype data for 116,330 ENU-induced mutations in the Mutagenetix database, we calculate that putative null mutations, and PolyPhen-2-classified “probably damaging”, “possibly damaging”, or “probably benign” mutations have, respectively, 61%, 17%, 9.8%, and 4.5% probabilities of causing phenotypically detectable damage in the homozygous state. We use these probabilities in the estimation of genome saturation and the probability that in idual proteins have been adequately tested for function in specific genetic screens. We estimate the proportion of essential autosomal genes in Mus musculus (C57BL/6J) and show that viable mutations in essential genes are more likely to induce phenotype than mutations in non-essential genes.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2021
DOI: 10.1038/S41467-020-20851-4
Abstract: Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638 , CLIC5, SLC2A12, YAP1, MXRA5 , and SMAD6 . Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.
Publisher: Wiley
Date: 05-03-2020
DOI: 10.1111/CGE.13722
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.OGLA.2021.11.002
Abstract: Glaucoma is the leading cause of irreversible blindness worldwide however, vision loss resulting from glaucoma generally can be prevented through early identification and timely implementation of treatment. Recently, polygenic risk scores (PRSs) have shown promise in stratifying in idual risk and prognostication for primary open-angle glaucoma (POAG) to reduce disease burden. Integrating PRS testing into clinical practice is becoming increasingly realistic however, little is known about the attitudes of patients toward such testing. Cross-sectional, questionnaire-based study. Among the participants in the Australian and New Zealand Registry of Advanced Glaucoma, 2369 were invited to participate who fit the inclusion criteria of adults with a diagnosis of POAG who had not received genetic results that explain their condition, were not known to be deceased, resided in Australia, and had agreed to receive correspondence. One thousand one hundred sixty-nine in iduals (response rate, 49%) with POAG completed the survey evaluating their attitudes towards polygenic risk testing for glaucoma. Sociodemographic, health, perception, and emotional factors were examined to assess associations with interest in PRS testing. Interest in PRS testing was evaluated through assessing likelihood to take the test to predict personal risk of disease and disease severity, and whether the in idual would recommend the test to family members or others. Our results show strong interest in the test, with 69.4% of in iduals (798 of 1150) indicating a keenness in testing before diagnosis, had it been available. In particular, interest was seen in those from an urban area (odds ratio [OR], 1.70 95% confidence interval [CI], 1.15-2.49 P = 0.007), those who perceived their risk of developing glaucoma as higher (OR, 2.05 95% CI, 1.28-3.29 P = 0.003), and those who were worried about developing glaucoma (OR, 2.07 95% CI, 1.27-3.37 P = 0.004). People who were interested in testing were more likely to change their eye health-seeking intentions and to recommend testing to family members and others, as well as to undergo testing for prognostication. These findings will help to facilitate the clinical implementation of PRS testing for glaucoma to reduce irreversible vision loss.
Publisher: Informa UK Limited
Date: 16-08-2012
DOI: 10.4161/CC.21277
Publisher: Springer Science and Business Media LLC
Date: 26-06-2021
DOI: 10.1186/S12864-021-07782-0
Abstract: Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data. Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice ( TYRP1 , GPNMB , LYST , DCT , and MITF ). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP , and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls ( p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects. We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1016/J.COI.2006.01.001
Abstract: The generation of T cell receptor (TCR) sequence ersity is the strength of adaptive immunity, yet is also the Achilles' heel. To purge highly self-reactive T cells from the immune system, generation of ersity has coevolved with a mechanism of negative selection. Recent studies have revealed new insights addressing the why and how of negative selection by examining situations in which negative selection has failed in human and animals models of autoimmunity. Both thymocyte extrinsic and intrinsic mechanisms are required to restrict the TCR repertoire to a non-autoreactive set. Negative selection also ensures that T cells emerge with receptors that are focussed on the peptide moiety of MHC-peptide complexes.
Publisher: Public Library of Science (PLoS)
Date: 31-01-2013
Publisher: American Society for Clinical Investigation
Date: 06-06-2016
DOI: 10.1172/JCI85830
Publisher: American Medical Association (AMA)
Date: 2019
Publisher: American Medical Association (AMA)
Date: 04-2019
Publisher: Springer Science and Business Media LLC
Date: 02-11-2017
DOI: 10.1038/S41467-017-01342-5
Abstract: AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current ( I f ) and ryanodine receptor-derived diastolic local subsarcolemmal Ca 2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.
Publisher: Elsevier BV
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 08-03-2017
DOI: 10.1038/EJHG.2017.33
Publisher: Proceedings of the National Academy of Sciences
Date: 27-06-2011
Abstract: Precise control of the innate immune response is essential to ensure host defense against infection while avoiding inflammatory disease. Systems-level analyses of Toll-like receptor (TLR)-stimulated macrophages suggested that SHANK-associated RH domain-interacting protein (SHARPIN) might play a role in the TLR pathway. This hypothesis was supported by the observation that macrophages derived from chronic proliferative dermatitis mutation ( cpdm ) mice, which harbor a spontaneous null mutation in the Sharpin gene, exhibited impaired IL-12 production in response to TLR activation. Systems biology approaches were used to define the SHARPIN-regulated networks. Promoter analysis identified NF-κB and AP-1 as candidate transcription factors downstream of SHARPIN, and network analysis suggested selective attenuation of these pathways. We found that the effects of SHARPIN deficiency on the TLR2-induced transcriptome were strikingly correlated with the effects of the recently described hypomorphic L153P/ panr2 point mutation in Ikbkg [ N F-κB E ssential Mo dulator (NEMO)], suggesting that SHARPIN and NEMO interact. We confirmed this interaction by co-immunoprecipitation analysis and furthermore found it to be abrogated by panr2. NEMO-dependent signaling was affected by SHARPIN deficiency in a manner similar to the panr2 mutation, including impaired p105 and ERK phosphorylation and p65 nuclear localization. Interestingly, SHARPIN deficiency had no effect on IκBα degradation and on p38 and JNK phosphorylation. Taken together, these results demonstrate that SHARPIN is an essential adaptor downstream of the branch point defined by the panr2 mutation in NEMO.
Publisher: Oxford University Press (OUP)
Date: 28-07-2016
Abstract: PI3Ks have been identified as key signaling proteins involved in many basic biologic processes in health and disease. Transgenic animals have been essential tools to study the underlying molecular mechanisms in this context and therefore, have been widely used to elucidate the role of these factors in many different settings. More specifically, PI3Kγ, a subunit highly expressed in the hematopoietic system, has been implicated to play an important role in many inflammatory diseases as well as cancer. Here, we report identification of multiple, additional, previously unknown mutations in the genome of a widely used PI3Kγ-deficient (PI3Kγ−/−) mouse colony. These include a STOP mutation in the GM-CSFRα chain, leading to a complete and specific deficiency in GM-CSF signaling. PI3Kγ−/− animals consequently lacked alveolar macrophages (AMs) and succumbed rapidly to influenza virus infection. Furthermore, PI3Kγ−/− mice carried an additional mutation that affects mucin 2 (Muc2) transcripts. This protein is strongly involved in the regulation of colorectal cancer, and indeed, conflicting reports have indicated that PI3Kγ−/− animals spontaneously develop colorectal tumors. Thus, we uncover previously unknown, confounding factors present in a strain of PI3Kγ−/− mice, leading to additional deficiencies in important signaling pathways with potentially wide-ranging implications for the interpretation of previous studies. By separating the mutations, we established a unique Csf2ra−/− mouse model that allows us to study the role of cell intrinsic GM-CSFR signaling in vivo without confounding variables introduced by defective IL-5R and IL-3R signaling in mice lacking the common β chain (Csf2rb).
Publisher: Proceedings of the National Academy of Sciences
Date: 28-01-2010
Abstract: Null alleles of the gene encoding NEMO (NF-κB essential modulator) are lethal in hemizygous mice and men, whereas hypomorphic alleles typically cause a syndrome of immune deficiency and ectodermal dysplasia. Here we describe an allele of Ikbkg in mice that impaired Toll-like receptor signaling, lymph node formation, development of memory and regulatory T cells, and Ig production, but did not cause ectodermal dysplasia. Degradation of IκBα, which is considered a primary requirement for NEMO-mediated immune signaling, occurred normally in response to Toll-like receptor stimulation, yet ERK phosphorylation and NF-κB p65 nuclear translocation were severely impaired. This selective loss of function highlights the immunological importance of NEMO-regulated pathways beyond IκBα degradation, and offers a biochemical explanation for rare immune deficiencies in man.
Publisher: Frontiers Media SA
Date: 14-11-2019
Publisher: Elsevier BV
Date: 2023
DOI: 10.1016/J.AJO.2022.08.006
Abstract: To evaluate the relationship between body mass index (BMI) and glaucoma progression. Multicohort observational study. This study combined a retrospective longitudinal analysis of suspect and early manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. The BMI was then associated with glaucoma diagnosis and cross-sectional vertical cup-disc ratio (VCDR) measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study. In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (mean duration of monitoring (5.28 ± 1.80 years (10.6 ± 3.59 visits) (β 0.04 dB/year/SD95% CI [0.005, 0.069] P = .013). In the UK Biobank, a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (β -0.048/SD 95% CI [-0.056, 0.96] P < .001) and a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR 0.90 95% CI [0.84, 0.98] P = .011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR 0.94/SD 95% CI [0.91, 0.98] P = .002). Body mass index was also positively correlated with intraocular pressure (β 0.11/SD 95% CI [0.06, 0.15] P < .001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (β -0.007/SD 95% CI [-0.01, -0.001] P = .023). Body mass index correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.
Publisher: Proceedings of the National Academy of Sciences
Date: 11-2010
Abstract: Toll-like receptors (TLRs) trigger intestinal inflammation when the epithelial barrier is breached by physical trauma or pathogenic microbes. Although it has been shown that TLR-mediated signals are ultimately protective in models of acute intestinal inflammation [such as dextran sulfate sodium (DSS)-induced colitis], it is less clear which cells mediate protection. Here we demonstrate that TLR signaling in the nonhematopoietic compartment confers protection in acute DSS-induced colitis. Epithelial cells of MyD88/Trif-deficient mice express diminished levels of the epidermal growth factor receptor (EGFR) ligands hiregulin (AREG) and epiregulin (EREG), and systemic lipopolysaccharide administration induces their expression in the colon. N -ethyl- N -nitrosourea (ENU)-induced mutations in Adam17 (which is required for AREG and EREG processing) and in Egfr both produce a strong DSS colitis phenotype, and the Adam17 mutation exerts its deleterious effect in the nonhematopoietic compartment. The effect of abrogation of TLR signaling is mitigated by systemic administration of AREG. A TLR→MyD88→AREG/EREG→EGFR signaling pathway is represented in nonhematopoietic cells of the intestinal tract, responds to microbial stimuli once barriers are breached, and mediates protection against DSS-induced colitis.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Elsevier BV
Date: 11-2021
No related grants have been discovered for Owen Siggs.