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2022 ◽  
Vol 23 (2) ◽  
pp. 718
Author(s):  
Pol Andrés-Benito ◽  
Margarita Carmona ◽  
Mónica Jordán ◽  
Joaquín Fernández-Irigoyen ◽  
Enrique Santamaría ◽  
...  

Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula.


RNA Biology ◽  
2021 ◽  
pp. 1-13
Author(s):  
Sansi Xing ◽  
Jane Wang ◽  
Ruilin Wu ◽  
Marco M. Hefti ◽  
John F. Crary ◽  
...  

2021 ◽  
Vol 74 (6) ◽  
pp. 554-555
Author(s):  
Savita Devkatte ◽  
Mamta Janmeda ◽  
Santul Patel ◽  
TKS Rao ◽  
Vishnu Kharadi

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

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3124-3124
Author(s):  
Panagiotis Skendros ◽  
Irene Mavroudi ◽  
Stavros Papadakis ◽  
Peggy Kanellou ◽  
Erasmia Boutakoglou ◽  
...  

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.


2021 ◽  
Vol 7 (6) ◽  
pp. e632
Author(s):  
Peter Hackman ◽  
Salla M. Rusanen ◽  
Mridul Johari ◽  
Anna Vihola ◽  
Per Harald Jonson ◽  
...  

Background and ObjectivesTo determine the genetic cause of the disease in the previously reported family with adult-onset autosomal dominant distal myopathy (myopathy, distal, 3; MPD3).MethodsContinued clinical evaluation including muscle MRI and muscle pathology. A linkage analysis with single nucleotide polymorphism arrays and genome sequencing were used to identify the genetic defect, which was verified by Sanger sequencing. RNA sequencing was used to investigate the transcriptional effects of the identified genetic defect.ResultsSmall hand muscles (intrinsic, thenar, and hypothenar) were first involved with spread to the lower legs and later proximal muscles. Dystrophic changes with rimmed vacuoles and cytoplasmic inclusions were observed in muscle biopsies at advanced stage. A single nucleotide polymorphism array confirmed the previous microsatellite-based linkage to 8p22-q11 and 12q13-q22. Genome sequencing of three affected family members combined with structural variant calling revealed a small heterozygous deletion of 160 base pairs spanning the second last exon 10 of the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) gene, which is in the linked region on chromosome 12. Segregation of the mutation with the disease was confirmed by Sanger sequencing. RNA sequencing showed that the mutant allele produces a shorter mutant mRNA transcript compared with the wild-type allele. Immunofluorescence studies on muscle biopsies revealed small p62 and larger TDP-43 inclusions.DiscussionA small exon 10 deletion in the gene HNRNPA1 was identified as the cause of MPD3 in this family. The new HNRNPA1-related phenotype, upper limb presenting distal myopathy, was thus confirmed, and the family displays the complexities of gene identification.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yizhou Huang ◽  
Han Dai ◽  
Gangyi Yang ◽  
Lili Zhang ◽  
Shiyao Xue ◽  
...  

Abstract Background Congenital disorders of glycosylation (CDG) are a group of metabolic diseases with clinical and genetic heterogeneity, and CDG-IIg is one of the rare reported types of CDG. The aim of this study is to report the clinical manifestations and gene-phenotype characteristics of a rare case of CDG caused by a COG1 gene mutation and review literatures of CDG disease. Case presentation The patient was male, and the main clinical symptoms were developmental retardation, convulsion, strabismus, and hypoglycemia, which is rarely reported in CDG-IIg. We treated the patient with glucose infusion and he was recovered from hypoglycemia. Genetic analysis showed that the patient carried the heterozygous intron mutation c.1070 + 3A > G (splicing) in the coding region of the COG1 gene that was inherited from the mother, and the heterozygous mutation c.2492G > A (p. Arg831Gln) in exon 10 of the COG1 gene that was inherited from the father. The genes interacting with COG1 were mainly involved in the transport and composition of the Golgi. The clinical data and laboratory results from a patient diagnosed with CDG-IIg were analyzed, and the causative gene mutation was identified by high-throughput sequencing. The genes and signal pathways related to COG1 were analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Conclusions The c.2492G > A (p. Arg831Gln) mutation in exon 10 of the COG1 gene may be a potential pathogenetic variant for CDG-IIg. Because of the various manifestations of CDG in clinical practice, multidisciplinary collaboration is important for the diagnosis and treatment of this disease.


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

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.


Author(s):  
Yuan Liu ◽  
Shicun Huang ◽  
Liqiang Yu ◽  
Tan Li ◽  
Shanshan Diao ◽  
...  
Keyword(s):  

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