scholarly journals Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

2021 ◽  
Author(s):  
Kathryn R. Bowles ◽  
Derian A. Pugh ◽  
Laura-Maria Oja ◽  
Benjamin M. Jadow ◽  
Kurt Farrell ◽  
...  
Keyword(s):  
Exon 2 ◽  
Exon 10

scholarly journals SAT0527 COMBINED EFFECT OF COMMON VARIANTS IN EXON 2 OR EXON 3 AND A PATHOGENIC MUTATION IN EXON 10 OF THE MEDITERRANEAN FEVER GENE ON INFLAMMASOME ACTIVATION IN JAPANESE PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1221.2-1221
Author(s):  
T. Koga ◽  
Y. Endo ◽  
K. Furukawa ◽  
K. Agematsu ◽  
A. Yachie ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Japanese Patients ◽  
Pathogenic Mutation ◽  
Inflammasome Activation ◽  
Combined Effects ◽  
Common Variants ◽  
Thoracic Pain ◽  
Exon 2 ◽  
Mediterranean Fever ◽  
Exon 10

Background:Familial Mediterranean fever (FMF) is an autoinflammatory disease that is caused by Mediterranean fever (MEFV) gene mutations. It is characterized by recurrent and self-limiting febrile attacks within a short period. Although the pathologic significance ofMEFVexon 2 or exon 3 common variants in patients with FMF is modest and these variants are usually associated with less severe clinical presentations of FMF (1, 2), their combined effects with pathogenic mutation in exon 10 remain to be evaluated.Objectives:To determine the combined effect of common variants on clinical manifestations and inflammasome activity, we compared the clinical and laboratory characteristics between the coexistence and non-coexistence ofMEFVexon 2 or exon 3 variants in patients with FMF that had a heterozygousMEFVexon 10 mutation.Methods:We excluded patients with FMF that had twoMEFVexon 10 mutations in one or more alleles and those withMEFVvariants in exons other than in exons 2, 3, or 10. Finally, we reviewed 131 Japanese patients with FMF that had a heterozygousMEFVexon 10 mutation, and they were divided into the groups with and withoutMEFVexon 2 or exon 3 variants of 34 and 97, respectively. All enrolled patients had only a heterozygous M694I mutation in exon 10 of theMEFVgene. We measured serum IL-18 levels at remission without febrile attacks in the groups with and withoutMEFVexon 2 or exon 3 variants of 9 and 31, respectively.Results:In the univariate analysis, the group with variants in exon 2 or exon 3 had significantly earlier onset (16.0 years v.s. 20.5 years, p = 0.04), a higher percentage of thoracic pain with febrile attacks (68% v.s. 44%, p = 0.02), a higher frequency of attack (1.0/month v.s. 0.5/month, p = 0.02), and a higher IL-18 level in the serum at remission (606.3 pg/ml v.s. 168.4 pg/ml, p = 0.04, Figure 1) compared to the group without these variants. Importantly, multivariate analyses showed that the coexistence ofMEFVexon 2 or exon 3 variants and an exon 10 mutation was independently and significantly associated with earlier onset of FMF (p = 0.049) and thoracic pain (p = 0.03).Figure 1.Conclusion:Our results suggest that the coexistence ofMEFVexon 2 or exon 3 variants and aMEFVexon 10 mutation has combined effects on inflammasome activation in the Japanese population.References:[1]Migita K, Uehara R, Nakamura Y, et al. Familial Mediterranean fever in Japan. Medicine (Baltimore). 2012 Nov;91(6):337-43.[2]Shinar Y, Livneh A, Langevitz P, Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol. 2000;27(7):1703.Disclosure of Interests:None declared

scholarly journals Effects of different Familial Mediterranean Fever gene mutations and in vitro Colchicine treatment on Peripheral Blood Mononuclear Cells production of IL-6

2013 ◽  
Vol 12 (4) ◽  
pp. 370-377
Author(s):  
AK Daoud ◽  
WH Rajab ◽  
KM Alawneh ◽  
MA Nizar Harfiel
Keyword(s):  
Familial Mediterranean Fever ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Colchicine Treatment ◽  
Peripheral Blood Mononuclear ◽  
Exon 2 ◽  
Blood Mononuclear Cells ◽  
Mediterranean Fever ◽  
Exon 10

Rationale: We wanted to study the effects of Familial Mediterranean Fever (FMF) genetic mutations in Northern Jordan population and in vitro Colchicine treatment on the peripheral blood mononuclear cells (PBMN) production of IL-6 as a marker of disease activity. Methods: - 17 FMF patients and 9 controls were studied. (4 patients had exon 10 mutations only (M680I and V726A), 5 patients had exon 2 mutations (R202Q and E148Q) only and 8 patients with both exon mutations (compound homozygous or heterozygous M694V and R202Q). PBMN cells were incubated with Lipopolysaccharide at 100ng/ml or colchicine 10 ng/ml alone or both. Results: The results showed higher IL-6 levels in the FMF group than control for all treatment modalities, (108.97 vs. 56.49 ng/ml for unstimulated cells) with the highest levels when both exons are involved. Exon 10 mutations were associated with a higher IL-6 level than exon 2 mutations only. Exon 2 mutations alone also were associated with a higher than control IL-6 levels suggesting that it is not a polymorphism phenomenon and is involved in the pathogenesis. In vitro Colchicine treatment caused an increase in the production of IL-6 - although not as high as with LPS - for all groups. Conclusions: Mutations occurring in exon 10 are more significant than mutations occurring in exon 2, although both are contributing to the disease. However colchicine was associated with a paradoxical increase in IL-6 levels. This observation needs confirmation with different colchicine levels in the culture medium and warrants thinking about its exact mechanism of action. DOI: http://dx.doi.org/10.3329/bjms.v12i4.16659Bangladesh Journal of Medical Science Vol. 12 No. 04 October ’13 Page 370-377

The Levels of Tau Isoforms Containing Exon-2 and Exon-10 Segments Increased in the Cerebrospinal Fluids of the Patients with Sporadic Creutzfeldt-Jakob Disease

2015 ◽  
Vol 53 (6) ◽  
pp. 3999-4009 ◽  
Author(s):  
Cao Chen ◽  
Wei Zhou ◽  
Yan Lv ◽  
Qi Shi ◽  
Jing Wang ◽  
...  
Keyword(s):  
Exon 2 ◽  
Tau Isoforms ◽  
Jakob Disease ◽  
Exon 10

scholarly journals Increased Frequency of Mutations in the Gene Responsible for Familial Mediterranean Fever (MEFV) in a Cohort of Patients with Chronic Idiopathic Neutropenia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3124-3124
Author(s):  
Panagiotis Skendros ◽  
Irene Mavroudi ◽  
Stavros Papadakis ◽  
Peggy Kanellou ◽  
Erasmia Boutakoglou ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Mefv Gene ◽  
Genetic Alterations ◽  
Greek Population ◽  
Exon 2 ◽  
Mefv Mutations ◽  
Chronic Idiopathic Neutropenia ◽  
Mediterranean Fever ◽  
Reported Data ◽  
Exon 10

Abstract Introduction-Aim: Chronic idiopathic neutropenia (CIN) is a neutrophil disorder characterized by the prolonged and unexplained reduction in the number of peripheral blood (PB) absolute neutrophil counts (ANC). The underlying pathogenesis in CIN implicates the production of proinflammatory cytokines by activated lymphocytes and monocytes that induce excessive apoptotic death of the bone marrow (BM) granulocytic progenitor cells. Clonal hematopoiesis identified by next generation sequencing (NGS) of myeloid genes is found in 11% of CIN patients conferring an increased risk for MDS/AML transformation whereas the non-clonal patients display usually a benign course. The basis for the immune cell activation and proinflammatory cytokine production in CIN remains obscure. Based on previously reported data showing increased frequency of mutations of the MEFV gene encoding pyrin in patients with idiopathic inflammatory conditions other than typical Familial Mediterranean Fever (FMF), we sought to investigate the common MEFV mutations in a cohort of well characterized CIN patients. Patients-Methods: We have studied 50 patients fulfilling the previously reported diagnostic criteria of CIN (median ANC 1.5x10 9/L, range 0.2-1.7 x10 9/L), 44 females and 6 males with a median age of 56 years (range 25-87 years) and a long-follow-up (median 132 months, range 8-336 months) in the Department of Hematology of the University Hospital of Heraklion, Crete, Greece. Nonisotopic RNase cleavage assay (NIRCA) analysis was used as first screening method to detect MEFV exons 10 and 2 mutations in DNA extracted from PB or BM samples from CIN patients, confirmed by direct NGS analysis. These sequences contain the main disease-related mutations and polymorphisms. Results: Genetics alterations of MEFV were detected in 22 out of 50 CIN patients (44%). Pathogenic mutations (variants associated with typical or "atypical" FMF phenotype in Greek population) were identified in 10/50 CIN patients (20%). The 20% frequency of MEFV mutations in exon 10 and/or exon 2 in CIN patients is significantly higher compared to the carrier rate of common MEFV mutations in the healthy Greek population (0.7%) according to our previously reported data (P<0.0001, Fisher's exact test). NGS analysis confirmed the mutational pattern of NIRCA and specifically showed: (a) one patient with heterozygous I720M (ATC>ATG; Ile>Met), two patients with heterozygous A744S (GCC>TCC; Ala>Ser) and one with homozygosity, one patient with heterozygous M694V (ATG>GTG; Met>Val), one with heterozygous K695R (AAG>AGG; Lys>Arg) and one with heterozygous M680I (ATG>ATC; Met>Ile), all in exon 10, and (b) four patients with homozygous R202Q mutation in exon 2 (one patient with homozygous A744S co-mutation in exon 10) and two patients with R202Q heterozygosity combined with heterozygosity of I720M and A744S of exons 10, respectively. None of the patients displayed any symptoms/signs of FMF or other systemic inflammatory disease. No statistically significant differences were identified between MEFV mutated and non-mutated CIN patients in the severity of neutropenia or in lymphocyte, monocyte, hemoglobin and platelet counts. A significant difference was identified between the two patient groups in serum IgG (1440±264 vs 1133±245 mg/dl; P = 0.0023, Mann-Whitney test) but not IgA or IgM levels. Discussion: This study reports for the first time that 20% of unselected, consecutive patients with CIN carry mutations of the MEFV gene without clinical manifestations of FMF. Whether these patients represent atypical cases of FMF or the identified MEFV genetic alterations have a pathogenetic/modifying effect in the inflammatory responses associated with CIN is an open/novel field of research. As a first step we are currently investigating the neutrophil autophagic status, IL-1β production and the neutrophil extracellular trap (NET) formation in CIN patients with mutations in MEFV to clarify their potential effect in the immune deregulation known to characterize CIN. Disclosures No relevant conflicts of interest to declare.

Alternate Splicing Is a Frequent Event and Impacts Clinical Outcome in Myeloma: A High-Density Exon Array Analysis of Uniformly Treated Newly-Diagnosed Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 498-498 ◽  
Author(s):  
Nikhil C. Munshi ◽  
Cheng Li ◽  
Stephane Minvielle ◽  
Samir B Amin ◽  
Philippe Moreau ◽  
...  
Keyword(s):  
Overall Survival ◽  
Amyloid Beta ◽  
Exon Array ◽  
Newly Diagnosed ◽  
Alternate Splicing ◽  
Array Analysis ◽  
Exon 2 ◽  
Array Data ◽  
Human Exon ◽  
Exon 10

Abstract Alternate splicing is an important post translational change that alters specificity of gene function. Misregulation of alternative splicing has been implicated in number of disease processes including cancer. We have here analyzed alternate splicing in myeloma using high throughput exon array analysis. The GeneChip Human Exon 1.0 ST Arrays used in this investigation not only provides information on expression levels for genes, but as the probe sets are spread evenly over each exon, the array data also provides information on presence of each exon and identify recurrent alternately spliced genes. We conducted a study in series of 170 newly-diagnosed patients with multiple myeloma treated homogeneously in tandem transplantation IFM trials. RNA isolated from CD138 purified MM cells collected at the time of diagnosis were analyzed using the GeneChip Human Exon 1.0 ST Arrays. The dChip software was modified to analyze exon array data. We first normalized gene-level expression values across samples, and then identified differentially expressed exons between two sample groups. These exons are candidates for alternatively splicing events. We observed over 100 genes with candidate alternate splicing events, which have up or down-regulation of an exon relative to the baseline group in more than 20% patients. Dividing the group based on response, 52 alternately spliced exons were identified as influencing response to therapy. The genes and their exons with highest frequency of alternate splicing were CD79A exon 5 and 6, EDNRB exon 2, RASSF1 exon 8, CD1d exon9, TGFBetaRII exon 1, Calmin exon2, CEACAM1 exon 7, MADH1 exon 7, TBX5 exon 2, Amyloid beta exon 14, Nit protein 2 exon 10, Thymidylate synthetase exon 7. Amongst these genes, 32 genes had the most influence on response with over 50% differential frequency in patients achieving CR. Similarly we have identified 85 alternately spliced genes as influencing overall survival between groups divided by less than or more than 48 month survival. The genes with highest frequency of alternate splicing were NOTCH2 exon 18, CXCL3 exon 8, CD9 exon 3 Calmin exon 2, TIMELESS exon 12, SPOUTY homolog 1 exon 4, Amyloid beta exon 14, Nit protein 2 exon 10, Cyclin A2 exon7, lymphocyte antigen 6 exon 7. Forty-nine genes within this group had the most influence on overall survival. Number of spliced variants were shared between both response and survival groups suggesting their biological and functional significance. Further validation of these alternate splicing is under investigations. This study highlights significant frequency of alternate splicing and points to the need for evaluation of not only the expression level of genes but also post translational modifications. The genes identified here are important target for therapy as well as possible immune modulation.

P3-120: Mis-splicing of Tau Exon 2 and Exon 10 in myotonic dystrophy brain would result from different mechanisms

2011 ◽  
Vol 7 ◽  
pp. S553-S553
Author(s):  
Marie-Laure Caillet-Boudin ◽  
Claire-Marie Dhaenens ◽  
Marie-Lise Frandemiche ◽  
Helene Tran ◽  
Celine Carpentier ◽  
...  
Keyword(s):  
Myotonic Dystrophy ◽  
Exon 2 ◽  
Exon 10

scholarly journals Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD

2021 ◽  
Author(s):  
Kathryn R. Bowles ◽  
Derian A. Pugh ◽  
Laura-Maria Oja ◽  
Benjamin M. Jadow ◽  
Kurt Farrell ◽  
...  
Keyword(s):  
Temporal Cortex ◽  
Mrna Splicing ◽  
Human Brain Tissue ◽  
Gene Encoding ◽  
Exon 2 ◽  
Combinatorial Regulation ◽  
Splicing Regulators ◽  
Microtubule Binding Domain ◽  
Exon 10

ABSTRACTUnderstanding regulation of MAPT splicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions. MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using an unbiased correlational screen in human brain tissue, we observed coordination of MAPT exons 2 and 10 splicing. Expression of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.

scholarly journals R761H M694I, M694V, V726A, R202Q, M680I AND E148Q MEFV GENE (FAMILIAL MEDITERRANEAN FEVER GENE) MUTATIONS IN THE AZERBAIJANİAN PATİENTS

2021 ◽  
Vol 06 (01) ◽  
pp. 50-51
Author(s):  
Huseynova Lala Huseynova Lala ◽  
Huseynova Qumru Huseynova Qumru
Keyword(s):  
Familial Mediterranean Fever ◽  
Mediterranean Region ◽  
Phenotypic Variability ◽  
Mefv Gene ◽  
Eastern Mediterranean Region ◽  
Nucleotide Sequences ◽  
Exon 2 ◽  
Mediterranean Fever ◽  
The Republic ◽  
Exon 10

MEFV gene (Familial Mediterranean Fever Gene) is located on chromosome 16 - 16.13.3., and it is composed of 3,242,028-3,256,776 nucleotides. It is specified as having an autosome-recessive hereditary type. Autosome-dominant hereditary species were also recorded(2,4). The MEFV RoRet genes family contains exon 10, consisting of 10,000 nucleotide sequences(5). The length of the transcript consists of 3.7 thousand nucleotide sequences consisting of 761 synthesized pyridine protein amino acid bases(1,3) MEFV gene researches were performed in the population of the Republic of Azerbaijan. Over 80 mutations have been identified so far. Four missense mutations (M680I, M694V, M694I, and V726A) in exon 10, together with E148Q in exon 2, account for the majority of FMF mutations in populations originating from areas around the eastern Mediterranean region. The various combinations of MEFV mutations are largely associated with the phenotypic variability of the disease. The most serious complication of FMF is the development of renal amyloidosis, which may be the only manifestation of the disease. The molecular-genetic study of the MEFV gene isolated from the genome DNA of 18 patients suspected of Family Disease Fever has identified 7 mutations: R761H M694I, M694V, V726A, R202Q, M680I and E148Q. All patients were of Azerbaijan origin, from the Mediterranean region of Azerbaijan. They were evaluated for clinical findings and family history of FMF. Seven mutations of MEFV gene were identified in heterozygous, homozygous and compound conditions: R761H M694I, M694V, V726A, R202Q, M680I and E148Q. The mutations E148Q and R202Q were discovered in exon 2 and R761H M694I, M694V, V726A, M680I were found in exon10 in the population of the Republic of Azerbaijan.

Association of polymorphisms in exons 2 and 10 of the insulin-like growth factor 2 (IGF2) gene with milk production traits in Polish Holstein-Friesian cattle

2009 ◽  
Vol 77 (1) ◽  
pp. 37-42 ◽  
Author(s):  
Emilia Bagnicka ◽  
Eulalia Siadkowska ◽  
Nina Strzałkowska ◽  
Beata Żelazowska ◽  
Krzysztof Flisikowski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Milk Production ◽  
Insulin Like Growth Factor ◽  
Nucleotide Polymorphisms ◽  
Production Traits ◽  
Milk Production Traits ◽  
Milk Traits ◽  
Exon 2 ◽  
Holstein Friesian ◽  
Exon 10

Insulin-like growth factor 2 (IGF2) is considered to be a regulator of post-natal growth and differentiation of the mammary gland. In the present work, associations of two single nucleotide polymorphisms in the bovine IGF2 gene with milk production traits were studied in dairy Holstein-Friesian cows: the already described g.8656C>T transition in exon 2 (RFLP-BsrI) and the newly found g.24507G>T transversion in exon 10 (RFLP-HaeIII), found by sequencing 273-bp exon 10 of the IGF2 gene in six individuals. Associations were analysed individually and in combination with the multi-trait repeatability test-day animal model. The CT/GT haplotype appeared to be associated with most of the milk traits studied (differences were significant at P⩽0·001). The most frequent CT/GG haplotype seemed inferior to others in fat and protein content and daily yield of fat and protein but superior (together with the TT/GG genotype) when the daily milk yield is considered.

RACIAL DIFFERENCES IN MLH1 AND MSH2 MUTATION: AN ANALYSIS OF YELLOW RACE AND WHITE RACE BASED ON THE INSIGHT DATABASE

2010 ◽  
Vol 08 (supp01) ◽  
pp. 111-125 ◽  
Author(s):  
WENQIAN WEI ◽  
LEI LIU ◽  
JIAN CHEN ◽  
KE JIN ◽  
FAN JIANG ◽  
...  
Keyword(s):  
Racial Differences ◽  
Hereditary Nonpolyposis Colorectal Cancer ◽  
International Database ◽  
Mlh1 Gene ◽  
Exon 2 ◽  
White Race ◽  
Hereditary Nonpolyposis ◽  
Exon 1 ◽  
Hereditary Tumors ◽  
Exon 10

MLH1 and MSH2 mutations underlie 90% of hereditary nonpolyposis colorectal cancer (HNPCC) mutations. The International Society of Gastrointestinal Hereditary Tumors (InSiGHT) has established an international database of mutations associated with HNPCC. Based on the InSiGHT database and the original references that reported the mutations, we analyzed the distributions of MLH1 and MSH2 mutations in yellow race and white race respectively and compared them subsequently. We found: (1) the distributions of mutation individuals in exon 1, 17 and 19 of MLH1 gene and in exon 2 of MSH2 gene showed significant differences between the two race groups (p < 0.05); (2) the distributions of mutation types in exon 2, 7 and 18 of MLH1 and exon 10 and 16 of MSH2 showed significant differences (p < 0.05); and (3) three mutations (c.649C > T, c.1625A > T and c.1721T > C) in MLH1 and five mutations (c.23C > T, c.187dupG, c.505A > G, c.1168C > T and c.2211-6T > C) in MSH2 have much higher frequency in yellow race than those in white race. Furthermore, three mutations (c.1453G > C, c.1742C > T and c.1758dupC) in MLH1 and two mutations (c.1255C > A and c.1886A > G) in MSH2 were only found in yellow race, which implies that specific mutations in yellow race need more attention when screening mutations in these two genes.

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