scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

Disordered haematopoiesis and cardiovascular disease: a focus on myelopoiesis

2018 ◽  
Vol 132 (17) ◽  
pp. 1889-1899 ◽  
Author(s):  
Dragana Dragoljevic ◽  
Marit Westerterp ◽  
Camilla Bertuzzo Veiga ◽  
Prabhakara Nagareddy ◽  
Andrew J. Murphy
Keyword(s):  
Inflammatory Diseases ◽  
Genetic Evidence ◽  
Loss Of Function ◽  
Atherosclerotic Vascular Disease ◽  
Stem And Progenitor Cells ◽  
Anti Inflammatory ◽  
The Cantos ◽  
Inflammatory Milieu ◽  
Proliferative Advantage

Cardiovascular (CV) diseases (CVD) are primarily caused by atherosclerotic vascular disease. Atherogenesis is mainly driven by recruitment of leucocytes to the arterial wall, where macrophages contribute to both lipid retention as well as the inflammatory milieu within the vessel wall. Consequently, diseases which present with an enhanced abundance of circulating leucocytes, particularly monocytes, have also been documented to accelerate CVD. A host of metabolic and inflammatory diseases, such as obesity, diabetes, hypercholesteraemia, and rheumatoid arthritis (RA), have been shown to alter myelopoiesis to exacerbate atherosclerosis. Genetic evidence has emerged in humans with the discovery of clonal haematopoiesis of indeterminate potential (CHIP), resulting in a disordered haematopoietic system linked to accelerated atherogenesis. CHIP, caused by somatic mutations in haematopoietic stem and progenitor cells (HSPCs), consequently provide a proliferative advantage over native HSPCs and, in the case of Tet2 loss of function mutation, gives rise to inflammatory plaque macrophages (i.e. enhanced interleukin (IL)-1β production). Together with the recent findings of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial that revealed blocking IL-1β using Canakinumab reduced CV events, these studies collectively have highlighted a pivotal role of IL-1β signalling in a population of people with atherosclerotic CVD. This review will explore how haematopoiesis is altered by risk-factors and inflammatory disorders that promote CVD. Further, we will discuss some of the recent genetic evidence of disordered haematopoiesis in relation to CVD though the association with CHIP and suggest that future studies should explore what initiates HSPC mutations, as well as how current anti-inflammatory agents affect CHIP-driven atherosclerosis.

scholarly journals A combined in silico, in vitro and clinical approach to characterise novel pathogenic missense variants in PRPF31 in retinitis pigmentosa

2018 ◽  
Author(s):  
Gabrielle Wheway ◽  
Liliya Nazlamova ◽  
Nervine Meshad ◽  
Samantha Hunt ◽  
Nicola Jackson ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
In Silico ◽  
Autosomal Dominant ◽  
Missense Variant ◽  
Incomplete Penetrance ◽  
Clinical Approach ◽  
Loss Of Function ◽  
Autosomal Dominant Retinitis Pigmentosa ◽  
Missense Variants

AbstractAt least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localise to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood.In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T>A, p.Ile114Asn.This work demonstrates how in silico modelling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.

scholarly journals Amyloid Proteins and Peripheral Neuropathy

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1553 ◽  
Author(s):  
Mohammed M. H. Asiri ◽  
Sjoukje Engelsman ◽  
Niels Eijkelkamp ◽  
Jo W. M. Höppener
Keyword(s):  
Peripheral Neuropathy ◽  
Potential Role ◽  
Inflammatory Diseases ◽  
Amyloid Proteins ◽  
Chronic Inflammatory Diseases ◽  
Histopathological Feature ◽  
Common Diseases ◽  
Biological Defects

Painful peripheral neuropathy affects millions of people worldwide. Peripheral neuropathy develops in patients with various diseases, including rare familial or acquired amyloid polyneuropathies, as well as some common diseases, including type 2 diabetes mellitus and several chronic inflammatory diseases. Intriguingly, these diseases share a histopathological feature—deposits of amyloid-forming proteins in tissues. Amyloid-forming proteins may cause tissue dysregulation and damage, including damage to nerves, and may be a common cause of neuropathy in these, and potentially other, diseases. Here, we will discuss how amyloid proteins contribute to peripheral neuropathy by reviewing the current understanding of pathogenic mechanisms in known inherited and acquired (usually rare) amyloid neuropathies. In addition, we will discuss the potential role of amyloid proteins in peripheral neuropathy in some common diseases, which are not (yet) considered as amyloid neuropathies. We conclude that there are many similarities in the molecular and cell biological defects caused by aggregation of the various amyloid proteins in these different diseases and propose a common pathogenic pathway for “peripheral amyloid neuropathies”.

A HoxD11 Homeobox Gene Mutation Associated With Congenital Absent Radius But Without The Thrombocytopenia Of The TAR Syndrome Or a HoxA11 Mutation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4837-4837
Author(s):  
Roger A. Fleischman
Keyword(s):  
Potential Role ◽  
Conflicts Of Interest ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Incomplete Penetrance ◽  
Potential Candidate ◽  
Negative Finding ◽  
Tar Syndrome ◽  
Absent Radius

HoxA11 and HoxD11 are homeobox genes critical for normal development of the forearm and thus are potential candidate genes for involvement in the pathogenesis of the thrombocytopenia/absent radius (TAR) syndrome. However, we previously reported an absence of coding sequence mutations in either HoxA11 or HoxD11 in a series of 10 unrelated TAR syndrome patients (Fleischman RA et al., Br J Haematol., 116:367-75, 2002). Despite this negative finding, interest in the potential role of homeobox genes in the TAR syndrome has been supported by a report of a HoxA11 mutation occurring in two kindreds with amegakaryocytic thrombocytopenia and radio-ulnar synostosis, a less pronounced more proximal pattern of radial malformation (Thompson AA and Nguyen LT. Nat Genet., 26:397-8, 2000). Unlike HoxA11, however, no mutations in the human HoxD11 gene have been described thus far that would help elucidate the potential role of this paralogous gene in megakaryopoiesis or the TAR syndrome. We now describe a novel mutation in human HoxD11 that results in a polyalanine sequence expansion, (GCG)6→ (GCG)8, and report that this mutation is associated with a unilateral absent radius in the affected propositus. A familial syndrome is suggested in this kindred, moreover, by the prior observation of a bilateral absent radius in a deceased maternal aunt. This mutation was not present in more than 100 unrelated normal subjects or 8 other unrelated individuals with sporadic absence of the radius. Two other living maternal relatives also carried the mutation but did not exhibit any radial defects, a finding consistent with autosomal dominance with incomplete penetrance, an inheritance pattern reported for short polyalanine expansion mutations in the related homeobox gene HoxD13 which cause synpolydactyly. In contrast to the reported HoxA11 mutation, however, neither the propositus nor the mutation carriers of this HoxD11 mutation exhibited thrombocytopenia or any other cytopenias or congenital defect. The results suggest that at least one class of mutation in human HoxD11 may be sufficient to cause an absent radius syndrome but unlike the reported HoxA11 mutation, does not adversely affect megakaryopoiesis. The findings further suggest that additional studies of the TAR syndrome may be necessary to exclude as yet undetected non-coding mutations in promoter or enhancer sequences that alter the expression of HoxA11, HoxD11 or other homeobox genes critical for radial development and/or megakaryopoiesis. This work was supported by a VA Merit Award. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The emerging role of C/EBPs in glucocorticoid signaling: lessons from the lung

2011 ◽  
Vol 212 (3) ◽  
pp. 291-305 ◽  
Author(s):  
Abraham B Roos ◽  
Magnus Nord
Keyword(s):  
Transcription Factors ◽  
Potential Role ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Steroid Resistance ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Glucocorticoid Signaling ◽  
Enhancer Binding Protein

Glucocorticoids (GCs) have been successfully used in the treatment of inflammatory diseases for decades. However, there is a relative GC resistance in several inflammatory lung disorders, such as chronic obstructive pulmonary disease (COPD), but still the mechanism(s) behind this unresponsiveness remains unknown. Interaction between transcription factors and the GC receptor contribute to GC effects but may also provide mechanisms explaining steroid resistance. CCAAT/enhancer-binding protein (C/EBP) transcription factors are important regulators of pulmonary gene expression and have been implicated in inflammatory lung diseases such as asthma, pulmonary fibrosis, cystic fibrosis, sarcoidosis, and COPD. In addition, several studies have indicated a role for C/EBPs in mediating GC effects. In this review, we discuss the different mechanisms of GC action as well as the function of the lung-enriched members of the C/EBP transcription factor family. We also summarize the current knowledge of the role of C/EBP transcription factors in mediating the effects of GCs, with emphasis on pulmonary effects, and their potential role in mediating GC resistance.

scholarly journals Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

2011 ◽  
Vol 208 (9) ◽  
pp. 1835-1847 ◽  
Author(s):  
Gwénola Boulday ◽  
Noemi Rudini ◽  
Luigi Maddaluno ◽  
Anne Blécon ◽  
Minh Arnould ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Vascular Lesions ◽  
Developmental Timing ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
The Central Nervous System ◽  
Dominant Condition

Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.

LRRK2 and vesicle trafficking

2012 ◽  
Vol 40 (5) ◽  
pp. 1117-1122 ◽  
Author(s):  
Giovanna Sanna ◽  
Maria Grazia Del Giudice ◽  
Claudia Crosio ◽  
Ciro Iaccarino
Keyword(s):  
Membrane Trafficking ◽  
Potential Role ◽  
Autosomal Dominant ◽  
Ashkenazi Jews ◽  
Dominant Form ◽  
Pathophysiological Role ◽  
Autosomal Dominant Form ◽  
Knockout Animals ◽  
The Brain

Mutations in LRRK2 (leucine-rich repeat kinase 2) (also known as PARK8 or dardarin) are responsible for the autosomal-dominant form of PD (Parkinson's disease). LRRK2 mutations were found in approximately 3–5% of familial and 1–3% of sporadic PD cases with the highest prevalence (up to 40%) in North Africans and Ashkenazi Jews. To date, mutations in LRRK2 are a major genetic risk factor for familial and sporadic PD. Despite the fact that 8 years have passed from the establishment of the first link between PD and dardarin in 2004, the pathophysiological role of LRRK2 in PD onset and progression is far from clearly defined. Also the generation of different LRRK2 transgenic or knockout animals has not provided new hints on the function of LRRK2 in the brain. The present paper reviews recent evidence regarding a potential role of LRRK2 in the regulation of membrane trafficking from vesicle generation to the movement along cytoskeleton and finally to vesicle fusion with cell membrane.

scholarly journals ThechbGGene of the Chitobiose (chb) Operon of Escherichia coli Encodes a Chitooligosaccharide Deacetylase

2012 ◽  
Vol 194 (18) ◽  
pp. 4959-4971 ◽  
Author(s):  
Subhash Chandra Verma ◽  
Subramony Mahadevan
Keyword(s):  
Escherichia Coli ◽  
Metal Binding ◽  
Inflammatory Diseases ◽  
Regulatory Protein ◽  
Loss Of Function ◽  
Content Type ◽  
Reading Frame ◽  
E Coli ◽  
Evolutionarily Conserved

ABSTRACTThechboperon ofEscherichia coliis involved in the utilization of the β-glucosides chitobiose and cellobiose. The function ofchbG(ydjC), the sixth open reading frame of the operon that codes for an evolutionarily conserved protein is unknown. We show thatchbGencodes a monodeacetylase that is essential for growth on the acetylated chitooligosaccharides chitobiose and chitotriose but is dispensable for growth on cellobiose and chitosan dimer, the deacetylated form of chitobiose. The predicted active site of the enzyme was validated by demonstrating loss of function upon substitution of its putative metal-binding residues that are conserved across the YdjC family of proteins. We show that activation of thechbpromoter by the regulatory protein ChbR is dependent on ChbG, suggesting that deacetylation of chitobiose-6-P and chitotriose-6-P is necessary for their recognition by ChbR as inducers. Strains carrying mutations inchbRconferring the ability to grow on both cellobiose and chitobiose are independent ofchbGfunction for induction, suggesting that gain of function mutations in ChbR allow it to recognize the acetylated form of the oligosaccharides. ChbR-independent expression of the permease and phospho-β-glucosidase from a heterologous promoter did not support growth on both chitobiose and chitotriose in the absence ofchbG, suggesting an additional role ofchbGin the hydrolysis of chitooligosaccharides. The homologs ofchbGin metazoans have been implicated in development and inflammatory diseases of the intestine, indicating that understanding the function ofE. colichbGhas a broader significance.

scholarly journals The Role of Autophagy in Immunity and Autoimmune Diseases / Uloga Autofagije U Imunskom Odgovoru I Autoimunskim Bolestima

2014 ◽  
Vol 15 (4) ◽  
pp. 223-229
Author(s):  
Bojana Simovic Markovic ◽  
Ljubica Vucicevic ◽  
Sanja Bojic ◽  
Vladislav Volarevic
Keyword(s):  
Autoimmune Diseases ◽  
Potential Role ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Physiological Role ◽  
Immune Functions ◽  
Complex Relationships ◽  
Cellular Components ◽  
Chaperone Mediated Autophagy

ABSTRACT Autophagy is a catabolic mechanism in the cell that involves the degradation of unnecessary or dysfunctional cellular components by the lysosomal machinery. Recent studies have indicated that autophagy is a source of autoantigens, thus highlighting its potential role in the pathogenesis of autoimmunity. There are at least three different forms of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). The physiological role of autophagy is to maintain cellular homeostasis by removing long-lived, damaged proteins and dysfunctional organelles and by providing energy. Aberrant autophagy may contribute to chronic inflammatory diseases and autoimmune diseases. An understanding of the complex relationships between autophagy and autophagy-related genes in each autoimmune disease creates the possibility of developing more specific and effective therapeutic strategies. Given the importance of autophagy in immune functions, this review article summarises current knowledge about the role of autophagy in the pathogenesis of autoimmune diseases.

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