16540
2016
eng
2073-2079
7
6
article
1
2018-07-23
--
--
Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients
Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
G3: Genes Genomes Genetics
10.1534/g3.116.030841
urn:nbn:de:bvb:20-opus-165405
G3: Genes Genomes Genetics, 2016, Vol. 6(7), p 2073-2079
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
A. Dessa Sadovnick
Anthony L. Traboulsee
Cecily Q. Bernales
Jay P. Ross
Amanda L. Forwell
Irene M. Yee
Lena Guillot-Noel
Bertrand Fontaine
Isabelle Cournu-Rebeix
Antonio Alcina
Maria Fedetz
Guillermo Izquierdo
Fuencisla Matesanz
Kelly Hilven
Bénédicte Dubois
An Goris
Ianire Astobiza
Iraide Alloza
Alfredo Antigüedad
Koen Vandenbroeck
Denis A. Akkad
Orhan Aktas
Paul Blaschke
Mathias Buttmann
Andrew Chan
Joerg T. Epplen
Lisa-Ann Gerdes
Antje Kroner
Christian Kubisch
Tania Kümpfel
Peter Lohse
Peter Rieckmann
Uwe K. Zettl
Frauke Zipp
Lars Bertram
Christina M. Lill
Oscar Fernandez
Patricia Urbaneja
Laura Leyva
Jose Carlos Alvarez-Cermeño
Rafael Arroyo
Aroa M. Garagorri
Angel García-Martínez
Luisa M. Villar
Elena Urcelay
Sunny Malhotra
Xavier Montalban
Manuel Comabella
Thomas Berger
Franz Fazekas
Markus Reindl
Mascha C. Schmied
Alexander Zimprich
Carles Vilariño-Güell
eng
uncontrolled
multiple sclerosis
eng
uncontrolled
genetics
eng
uncontrolled
linkage
eng
uncontrolled
association
eng
uncontrolled
plasminogen
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16540/068_Sadovnick_G3-GENES GENOMES GENETICS.pdf
13363
2012
eng
14
9
article
1
2016-05-17
--
--
Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients
Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity.
Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus.
Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%).
Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of <= 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades <= 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions >= 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.
Journal of Neuroinflammation
10.1186/1742-2094-9-14
urn:nbn:de:bvb:20-opus-133636
Journal of Neuroinflammation 2012, 9:14. doi:10.1186/1742-2094-9-14
Sven Jarius
Klemens Ruprecht
Brigitte Wildemann
Tania Kuempfel
Marius Ringelstein
Christian Geis
Ingo Kleiter
Christoph Kleinschnitz
Achim Berthele
Johannes Brettschneider
Kerstin Hellwig
Bernhard Hemmer
Ralf A. Linker
Florian Lauda
Christoph A. Hayrettin
Hayrettin Tumani
Arthur Melms
Corinna Trebst
Martin Stangel
Martin Marziniak
Frank Hoffmann
Sven Schippling
Jürgen H. Faiss
Oliver Neuhaus
Barbara Ettrich
Christian Zentner
Kersten Guthke
Ulrich Hofstadt-van Oy
Reinhard Reuss
Hannah Pellkofer
Ulf Ziemann
Peter Kern
Klaus P. Wandinger
Florian Then Bergh
Tobias Boettcher
Stefan Langel
Martin Liebetrau
Paulus S. Rommer
Sabine Niehaus
Christoph Münch
Alexander Winkelmann
Uwe K Zettl
Imke Metz
Christian Veauthier
Jörn P. Sieb
Christian Wilke
Hans P. Hartung
Orhan Aktas
Friedemann Paul
eng
uncontrolled
cerebrospinal-fluid
eng
uncontrolled
intractable hiccup
eng
uncontrolled
extensiv transverse myelitis
eng
uncontrolled
multiple sclerosis
eng
uncontrolled
anti-aquaporin-4 antibody
eng
uncontrolled
NMO-IGG
eng
uncontrolled
aquaporin-4 autoantibodies
eng
uncontrolled
immune-response
eng
uncontrolled
myasthenia gravis
eng
uncontrolled
immunoglobulin-G
Krankheiten
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13363/Jarius_1742-2094-9-14.pdf
20076
2020
eng
1
9
article
1
--
2020-01-10
--
The rare IL22RA2 signal peptide coding variant rs28385692 decreases secretion of IL-22BP isoform-1, -2 and -3 and is associated with risk for multiple sclerosis
The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10\(^{-4}\)). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%–60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.
Cells
2073-4409
10.3390/cells9010175
urn:nbn:de:bvb:20-opus-200769
swordwue
2020-03-06T10:40:13+00:00
attachment; filename=deposit.zip
ff20d7328934edf1e9a10066b8440b2b
Cells (2020) 9:1, 175. https://doi.org/10.3390/cells9010175
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Paloma Gómez-Fernández
Aitzkoa Lopez de Lapuente Portilla
Ianire Astobiza
Jorge Mena
Andoni Urtasun
Vivian Altmann
Fuencisla Matesanz
David Otaegui
Elena Urcelay
Alfredo Antigüedad
Sunny Malhotra
Xavier Montalban
Tamara Castillo-Triviño
Laura Espino-Paisán
Orhan Aktas
Mathias Buttmann
Andrew Chan
Bertrand Fontaine
Pierre-Antoine Gourraud
Michael Hecker
Sabine Hoffjan
Christian Kubisch
Tania Kümpfel
Felix Luessi
Uwe K. Zettl
Frauke Zipp
Iraide Alloza
Manuel Comabella
Christina M. Lill
Koen Vandenbroeck
eng
uncontrolled
IL22RA2
eng
uncontrolled
IL-22 binding protein isoform
eng
uncontrolled
mutation
eng
uncontrolled
signal peptide
eng
uncontrolled
multiple sclerosis
eng
uncontrolled
autoimmune
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20076/cells-09-00175.pdf