GNE
Ontology highlight
ABSTRACT:
PROVIDER: EGAO00000001029 | EGA |
REPOSITORIES: EGA
Publications
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
Mariathasan Sanjeev S Turley Shannon J SJ Nickles Dorothee D Castiglioni Alessandra A Yuen Kobe K Wang Yulei Y Kadel Edward E EE Koeppen Hartmut H Astarita Jillian L JL Cubas Rafael R Jhunjhunwala Suchit S Banchereau Romain R Yang Yagai Y Guan Yinghui Y Chalouni Cecile C Ziai James J Şenbabaoğlu Yasin Y Santoro Stephen S Sheinson Daniel D Hung Jeffrey J Giltnane Jennifer M JM Pierce Andrew A AA Mesh Kathryn K Lianoglou Steve S Riegler Johannes J Carano Richard A D RAD Eriksson Pontus P Höglund Mattias M Somarriba Loan L Halligan Daniel L DL van der Heijden Michiel S MS Loriot Yohann Y Rosenberg Jonathan E JE Fong Lawrence L Mellman Ira I Chen Daniel S DS Green Marjorie M Derleth Christina C Fine Gregg D GD Hegde Priti S PS Bourgon Richard R Powles Thomas T
Nature 20180214 7693
Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer wh ...[more]
Similar Datasets
Project description:The GNE gene encodes the rate-limiting, bifunctional enzyme of sialic acid biosynthesis, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). Biallelic GNE mutations underlie GNE myopathy, an adult-onset progressive myopathy. GNE myopathy-associated GNE mutations are predominantly missense, resulting in reduced, but not absent, GNE enzyme activities. The exact pathomechanism of GNE myopathy remains unknown, but likely involves aberrant (muscle) sialylation. Here, we summarize 154 reported and novel GNE variants associated with GNE myopathy, including 122 missense, 11 nonsense, 14 insertion/deletions, and seven intronic variants. All variants were deposited in the online GNE variation database (http://www.dmd.nl/nmdb2/home.php?select_db=GNE). We report the predicted effects on protein function of all variants well as the predicted effects on epimerase and/or kinase enzymatic activities of selected variants. By analyzing exome sequence databases, we identified three frequently occurring, unreported GNE missense variants/polymorphisms, important for future sequence interpretations. Based on allele frequencies, we estimate the world-wide prevalence of GNE myopathy to be ?4-21/1,000,000. This previously unrecognized high prevalence confirms suspicions that many patients may escape diagnosis. Awareness among physicians for GNE myopathy is essential for the identification of new patients, which is required for better understanding of the disorder's pathomechanism and for the success of ongoing treatment trials.
| S-EPMC4172345 | biostudies-literature
Project description:GNE myopathy is a rare, recessively inherited, early adult-onset myopathy, characterized by distal and proximal muscle degeneration which often spares the quadriceps. It is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE). This study aimed to identify the disease-causing mutation in a three-generation Han-Chinese family with members who have been diagnosed with myopathy. A homozygous missense mutation, c.1627G>A (p.V543M) in the GNE gene co-segregates with the myopathy present in this family. A GNE myopathy diagnosis is evidenced by characteristic clinical manifestations, rimmed vacuoles in muscle biopsies and the presence of biallelic GNE mutations. This finding broadens the GNE gene mutation spectrum and extends the GNE myopathy phenotype spectrum.
| S-EPMC6201217 | biostudies-other
Project description:BackgroundGNE myopathy is a rare distal myopathy caused by mutations of the GNE gene. A few cases of GNE myopathy accompanied by neurogenic features of electrophysiology mimicking hereditary motor neuropathy were reported recently. We confirmed this feature and described the clinical phenotype and mutations of GNE myopathy in these rare cases.ResultsThe absence of lower limb tendon reflexes, decreased compound muscle action potentials in lower leg motor nerves, and neurogenic pattern of electromyography suggested neuropathy in four patients. However, muscle pathology revealed a predominantly myogenic pattern. The follow-up electroneurography results implied that the compound motor action potential amplitudes deteriorated over time. Next-generation sequencing identified three novel variants of the GNE gene, c.2054T > C (p.Val685Ala), c.424G > A (p.Gly142Arg) and c.944T > C (p.Phe315Ser), as well as two hotspot mutations, c.115C > T(p.Arg39*) and c.620A > T(p.Asp207Val), in these patients. These novel mutations cosegregated with disease in the family.ConclusionsThese rare cases supported the existence of neurogenic features of electrophysiology different from the typical myopathic pattern of GNE myopathy.
| S-EPMC9118620 | biostudies-literature
Project description:GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions.We performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation.We report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon-intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3-kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion.We have identified GNE as one of the genes susceptible to Alu-mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.
| S-EPMC5511805 | biostudies-literature
Project description:GNE myopathy is an autosomal recessive muscle disease caused by biallelic mutations in GNE, a gene encoding for a single protein with key enzymatic activities, UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase, in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities' muscles, with marked sparing of the quadriceps. Characteristic findings on biopsies of affected muscles include 'rimmed' (autophagic) vacuoles, aggregation of various proteins and fibre size variation. The diagnosis is confirmed by sequencing of the GNE gene. Note that we use a new mutation nomenclature based on the longest transcript (GenBank: NM_001128227), which encodes a 31-amino acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Based upon the pathophysiology of the disease, recent clinical trials as well as early gene therapy trials have evaluated the use of sialic acid or N-acetylmannosamine (a precursor of sialic acid) in patients with GNE myopathy. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.
| S-EPMC4394625 | biostudies-literature
Project description:GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic "rimmed" vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.
| S-EPMC6277305 | biostudies-literature
Project description:This experiment contains a subset of data from the BLUEPRINT Epigenome project ( http://www.blueprint-epigenome.eu ), which aims at producing a reference haemopoetic epigenomes for the research community. 29 samples of primary cells or cultured primary cells of different haemopoeitc lineages from cord blood are included in this experiment. This ArrayExpress record contains only meta-data. Raw data files have been archived at the European Genome-Phenome Archive (EGA, www.ebi.ac.uk/ega) by the consortium, with restricted access to protect sample donors' identity. The relevant accessions of EGA data sets is EGAD00001001165. Details on how to apply for data access via the BLUEPRINT data access committee are on the EGA data set pages. The mapping of samples to these EGA accessions can be found in the 'Sample Data Relationship Format' file of this ArrayExpress record. Information on individual samples and sequencing libraries can also be found on the BLUEPRINT data coordination centre (DCC) website: http://dcc.blueprint-epigenome.eu
2015-09-30 | E-MTAB-3819 | biostudies-arrayexpress
Project description:This experiment contains a subset of data from the BLUEPRINT Epigenome project ( http://www.blueprint-epigenome.eu ), which aims at producing a reference haemopoetic epigenomes for the research community. 4 samples of primary cells from tonsil with cell surface markes CD20med/CD38high in young individuals (3 to 10 years old) are included in this experiment. This ArrayExpress record contains only meta-data. Raw data files have been archived at the European Genome-Phenome Archive (EGA, www.ebi.ac.uk/ega) by the consortium, with restricted access to protect sample donors' identity. The relevant accessions of EGA data sets is EGAD00001001523. Details on how to apply for data access via the BLUEPRINT data access committee are on the EGA data set pages. The mapping of samples to these EGA accessions can be found in the 'Sample Data Relationship Format' file of this ArrayExpress record. Information on individual samples and sequencing libraries can also be found on the BLUEPRINT data coordination centre (DCC) website: http://dcc.blueprint-epigenome.eu
2016-05-12 | E-MTAB-4754 | biostudies-arrayexpress
Project description:GNE myopathy is a distal myopathy caused by biallelic variants in GNE, which encodes a protein involved in sialic acid biosynthesis. Compound heterozygosity of the second most frequent variant among Japanese GNE myopathy patients, GNE c.620A>T encoding p.D207V, occurs in the expected number of patients; however, homozygotes for this variant are rare; three patients identified while 238 homozygotes are estimated to exist in Japan. The aim of this study was to elucidate the pathomechanism caused by c.620A>T. Identity-by-descent mapping indicated two distinct c.620A>T haplotypes, which were not correlated with age onset or development of myopathy. Patients homozygous for c.620A>T had mildly decreased sialylation, and no additional pathogenic variants in GNE or abnormalities in transcript structure or expression of other genes related to sialic acid biosynthesis in skeletal muscle. Structural modeling of full-length GNE dimers revealed that the variant amino acid localized close to the monomer interface, but far from catalytic sites, suggesting functions in enzymatic product transfer between the epimerase and kinase domains on GNE oligomerization. In conclusion, homozygotes for c.620A>T rarely develop myopathy, while symptoms occur in compound heterozygotes, probably because of mildly decreased sialylation, due to partial defects in oligomerization and product trafficking by the mutated GNE protein.
| S-EPMC9758176 | biostudies-literature