scholarly journals PYPAF1 nonsense mutation in a patient with an unusual autoinflammatory syndrome: Role of PYPAF1 in inflammation

2006 ◽  
Vol 54 (2) ◽  
pp. 508-514 ◽  
Author(s):  
I. Jéru ◽  
H. Hayrapetyan ◽  
P. Duquesnoy ◽  
T. Sarkisian ◽  
S. Amselem
Keyword(s):  
Nonsense Mutation ◽  
Autoinflammatory Syndrome

scholarly journals The inlA Gene of Listeria monocytogenesLO28 Harbors a Nonsense Mutation Resulting in Release of Internalin

1998 ◽  
Vol 66 (7) ◽  
pp. 3420-3422 ◽  
Author(s):  
Renaud Jonquières ◽  
Hélène Bierne ◽  
Jérôme Mengaud ◽  
Pascale Cossart
Keyword(s):  
Cell Adhesion ◽  
Listeria Monocytogenes ◽  
Virulence Factor ◽  
Adhesion Molecule ◽  
Nonsense Mutation ◽  
Cell Adhesion Molecule ◽  
Culture Medium ◽  
Surface Protein ◽  
Truncated Protein

ABSTRACT Internalin is a surface protein that mediates entry ofListeria monocytogenes EGD into epithelial cells expressing the cell adhesion molecule human E-cadherin or its chicken homolog, L-CAM, which act as receptors for internalin. After observing that entry of L. monocytogenes LO28 into S180 fibroblasts, in contrast to that of EGD, did not increase after transfection with L-CAM, we examined both the expression and the structure of internalin in strain LO28. We discovered a nonsense mutation in inlA which results in a truncated protein released in the culture medium. Mutations leading to release of internalin were also detected in clinical and food isolates. These results question the role of internalin as a virulence factor in murine listeriosis.

scholarly journals α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Pablo Agüero ◽  
María José Sainz ◽  
María-Salud García-Ayllón ◽  
Javier Sáez-Valero ◽  
Raquel Téllez ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Genetic Model ◽  
Late Onset ◽  
Future Research ◽  
Clinical Genetic ◽  
Csf Analysis ◽  
Amyloidogenic Processing ◽  
Age Related ◽  
Spanish Cohort

Abstract Background The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive. Methods Clinical-genetic and biomarker study of a first family with early- and late-onset AD associated with a nonsense ADAM10 mutation (p.Tyr167*). CSF analysis included AD core biomarkers, as well as Western blot of ADAM10 species and sAPPα and sAPPβ peptides. We evaluate variant’s pathogenicity, pattern of segregation, and further screened for the p.Tyr167* mutation in 197 familial AD cases from the same cohort, 200 controls from the same background, and 274 AD cases from an independent Spanish cohort. Results The mutation was absent from public databases and segregated with the disease. CSF Aβ42, total tau, and phosphorylated tau of affected siblings were consistent with AD. The predicted haploinsufficiency effect of the nonsense mutation was supported by (a) ADAM10 isoforms in CSF decreased around 50% and (b) 70% reduction of CSF sAPPα peptide, both compared to controls, while sAPPβ levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα and sAPPβ levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings. The p.Tyr167* mutation was not found in any of the other AD cases or controls screened. Conclusions This family illustrates the role of ADAM10 in the amyloidogenic process and the clinical development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model for sporadic late-onset AD due to age-related downregulation of α-secretase. This report encourages future research on ADAM10 enhancers.

Novel nonsense mutation inMSX1in familial nonsyndromic oligodontia: subcellular localization and role of homeodomain/MH4

2013 ◽  
Vol 122 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Masashi Kimura ◽  
Junichiro Machida ◽  
Seishi Yamaguchi ◽  
Akio Shibata ◽  
Tadashi Tatematsu ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Nonsense Mutation

scholarly journals Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models

RMD Open ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. e001824
Author(s):  
Dan Lévy ◽  
Alexandre Mariotte ◽  
Aurore DeCauwer ◽  
Cecile Macquin ◽  
Angélique Pichot ◽  
...  
Keyword(s):  
Mouse Models ◽  
Ex Vivo ◽  
Joint Inflammation ◽  
Autoinflammatory Syndrome ◽  
Her Family ◽  
Whole Exome ◽  
Urate Crystals

ObjectiveTo explore at the molecular level the phenotype of a patient suffering an autoinflammatory syndrome which was diagnosed as familial cold autoinflammatory syndrome type 2 (FCAS-2). To explore the functions of Nlrp12 in inflammation using mouse models.MethodsWhole exome sequencing and Nlrp12 targeted resequencing were performed on DNA isolated from the patient and her family members. In vivo and ex vivo models of inflammation (urate crystals-dependent acute joint inflammation and urate crystals-induced peritonitis) were analysed in Nlrp12-deficient and Nlrp12-competent mice.ResultsA rare missense NLRP12 variant (c.857C>T, p.P286L) was identified in the patient and her healthy relatives. Nlrp12-deficient mice exhibit reduced systemic inflammation and neutrophilic infiltration.ConclusionNlrp12 mediates proinflammatory functions in mice. In humans, the identification of Nlrp12 variants must be cautiously interpreted depending on clinical and paraclinical data to diagnose FCAS-2.

scholarly journals The relationship between deficit in digit span and genotype in nonsense mutation Duchenne muscular dystrophy

Neurology ◽  
2018 ◽  
Vol 91 (13) ◽  
pp. e1215-e1219 ◽  
Author(s):  
Mathula Thangarajh ◽  
Gary L. Elfring ◽  
Panayiota Trifillis ◽  
Joseph McIntosh ◽  
Stuart W. Peltz ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cognitive Deficits ◽  
Nonsense Mutation ◽  
Digit Span ◽  
Critical Role ◽  
Alternative Promoters ◽  
Significant Difference ◽  
The Relationship

ObjectiveTo evaluate the relationship between deficit in digit span and genotype in nonsense mutation (nm) Duchenne muscular dystrophy (DMD) (nmDMD).MethodsWe investigated the relationship between normalized digit-span forward (d-sf) and digit-span backward (d-sb) scores to the location of nmDMD mutations in 169 participants ≥5 to ≤20 years who participated in a phase 2b clinical trial. Because alternative promoters are found upstream of DMD exons 30, 45, and 63, we correlated d-sf and d-sb to the specific nmDMD mutation location.ResultsParticipants with nm downstream of exon 30, downstream of exon 45, and downstream of exon 63 had significantly lower normalized d-sf scores (p < 0.0001). Participants with nm downstream of exon 45 in addition had significantly lower normalized d-sb score (p < 0.04). There was no significant difference in the normalized d-sb score in participants with mutations upstream or downstream of DMD exon 30 or upstream or downstream of DMD exon 63.ConclusionOur data provide evidence that specific cognitive deficits correlate to genotype in individuals with nmDMD, highlighting the critical role of brain-specific dystrophin isoforms in the neurobiological manifestations of this disease.Clinicaltrials.gov identifierNCT02090959.

4 SUBFERTILITY IN BULLS CARRYING A NONSENSE MUTATION IN TMEM95 IS DUE TO FAILURE TO PENETRATE THE ZONA PELLUCIDA

2017 ◽  
Vol 29 (1) ◽  
pp. 109 ◽  
Author(s):  
B. Fernandez-Fuertes ◽  
S. Kölle ◽  
P. Lonergan
Keyword(s):  
Reproductive Performance ◽  
Zona Pellucida ◽  
Nonsense Mutation ◽  
Genome Wide Association Study ◽  
Transmembrane Protein ◽  
Sperm Concentration ◽  
Sperm Function ◽  
Cleavage Rate ◽  
Cell Stage

In a recent genome-wide association study, male reproductive ability was assessed for 7962 Fleckvieh sires (Pausch et al. 2014 PLoS Genet. 10, e1004044). Forty bulls in the population with exceptionally poor reproductive performance were found to be homozygous for a nonsense mutation in the transmembrane protein 95 (TMEM95)-encoding gene. Ejaculates from these individuals exhibited normal sperm concentration, morphology, viability, and motility. However, out of 35,671 inseminations with these bulls, only 1.7% resulted in pregnancies. In addition, none of the bulls with normal reproductive performance was homozygous for this mutation. The aim of this study was to examine the effect of this nonsense mutation in TMEM95 on bovine sperm function in vitro. In all experiments, data were assessed for normality of distribution and analysed using a one-way ANOVA. The model included the main effects of treatment, replicate and their interactions. In Experiment 1, the fertilizing ability of sperm, assessed as oocyte cleavage rate, from 5 homozygous (mt/mt), 3 heterozygous (wt/mt), and 2 wildtype (wt/wt) Fleckvieh bulls was assessed. Oocytes fertilised with sperm from mt/mt males had a lower cleavage rate at 48 h post-fertilization than oocytes fertilised with sperm from wt/wt or wt/mt bulls (26 ± 3%, 72 ± 2%, and 79 ± 3%, respectively; P < 0.01). In addition, the kinetics of cleavage were slower in the mt/mt group as evidenced by a lower proportion of embryos beyond the 2-cell stage at 48 h (32 ± 12.6%, 90 ± 3.6%, and 87 ± 0.4%, respectively, P < 0.01). This translated into a lower blastocyst rate at Day 8 in the mt/mt group in comparison with wt/mt and wt/wt groups (2 ± 1%, 27 ± 3%, and 40 ± 2%, respectively, P < 0.01). In Experiment 2, fluorescent staining of oocytes 3 h after fertilization revealed a lower number of sperm from mt/mt bulls bound to the zona pellucida (ZP) in comparison with sperm from wt/wt or wt/mt individuals (3 ± 1.0, 11 ± 2.3, and 24 ± 9.4, respectively; P < 0.05). In order to further study the potential role of TMEM95 in sperm-ZP interaction, in Experiment 3 sperm from the 3 groups were used to fertilize ZP-free oocytes. Consistent with the previous results, sperm from mt/mt bulls were less able to penetrate oocytes with no ZP than sperm from wt/wt or wt/mt bulls (6 ± 2%, 44 ± 8%, and 68 ± 14%, respectively; P < 0.05). In conclusion, these results suggest that TMEM95 is involved in events that take place before ZP binding but are required for sperm to interact normally with the oocyte vestments and, ultimately, to achieve fertilization. Further study of the possible role of this protein in the initiation of sperm capacitation and hypermotility, as well as in early embryo development, will shed more light regarding the crucial role of TMEM95 in sperm function. Supported by the Irish Department of Agriculture, Food and The Marine under the Research Stimulus Programme (Grant No. 11 S 104).

The Critical Role of Kindlin-3 in Intiation of Physiological Thrombus Formation ~ Analysis of Kindlin-3 Deficient Patient

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1062-1062
Author(s):  
Hisashi Kato ◽  
Shigenori Honda ◽  
Hirokazu Kashiwagi ◽  
Nobuko Nishiura ◽  
Keigo Akuta ◽  
...  
Keyword(s):  
Cell Line ◽  
Nonsense Mutation ◽  
Thrombus Formation ◽  
Severe Bleeding ◽  
Sequencing Analysis ◽  
Aggregate Formation ◽  
Hel Cells ◽  
Healthy Control ◽  
Inside Out

Background: Kindlin-3 which is expressed mainly in hematopoietic cells, is essential for platelet fibrinogen receptor integrin αIIbβ3 (GPIIb-IIIa) activation and kindlin-3 deficiency causes severe bleeding problems. αIIbβ3 activation is tightly regulated by inside-out signaling, and the direct interaction of talin and kindlin-3 with β3-cytoplasmic tail following CalDAG-GEFI-induced Rap1 activation is critical for αIIbβ3 activation. We have reported that immediate and sustained αIIbβ3 activation by inside-out signaling is important for thrombus formation under physiological conditions (Blood 2016). However, the details of inside-out signaling are not still fully understood. Recently we identified patient with kindlin-3 deficiency as the first Japanese patient with kindlin-3 deficiency caused by novel p.W277X nonsense mutation. To clarify the role of kindlin-3 and the molecular mechanism of inside-out signaling, we analyzed single platelet behavior adhered on collagen under physiological flow conditions, and established kindlin-3 deficient human erythroleukemia HEL cell line. Case: The patient was 8-month old female, born to Japanese consanguineous parents. She has been suffering from bleeding tendency shortly after birth. Her peripheral blood showed slightly decreased platelet count (95x103/L), anemia (Hb 6.9 g/L), and elevated leukocyte count of 37.2x106/L with 1.0% blast. Although the surface expressions of glycoproteins were comparable to healthy control, her platelet aggregations and αIIbβ3 activation were strongly impaired in all agonist stimulations due to defective kindlin-3 expression. The sequencing analysis revealed the homozygous novel nonsense mutation, p.W277X (c.918G>A) in kindlin-3. Methods: Human platelets were obtained from healthy control subjects (CT) and patients with kindlin-3 deficiency and Glanzmann thrombasthenia (GT). Whole blood was perfused at a shear rate 1,250s-1 on collagen surface and shear-induced in vitro thrombus formation during 10 minutes was observed. To evaluate the single platelet behavior after the initial attachment on collagen, each single platelet was analyzed by CellTracker software (Pccinini F. et al. Bioinformatics 2015). To further determine the role of kindlin-3 in inside-out signaling, Kindlin-3 was knocked out by CRISPR-Cas9 system and established kindlin-3 deficient HEL cell line. Results: First, we compared shear-induced thrombus formation between CT, GT, and kindlin-3 deficiency. In contrast to the stable and large platelet aggregate formation in CT after 10 minutes blood perfusion, almost no aggregate was observed in both GT and Kindlin-3 deficiency. In kindlin-3 deficiency, the initial platelet attachment on collagen seemed comparable to that of CT and GT. However, the single adherent platelets looked unstable. Next, we determined the behavior of initially attached platelets. Between CT, GT, and kindlin-3 deficiency, the numbers of platelets attached on collagen during 10 seconds were comparable. Between the initially attached platelets, 31.25% of CT platelets formed stable adhesion followed by platelet aggregation. Similar to CT, 33% of GT platelets adhered stably. However, these GT platelets did not proceed to aggregate formation due to αIIbβ3 deficiency. In contrast to GT, kindlin-3 deficient platelets showed increased detachment, only 9% of initially attached platelets stably adhered. These results suggest that kindlin-3 is indispensable for platelet initial adhesion to collagen by integrin α2β1 activation and explains severe bleeding symptoms in kindlin-3 deficiency than GT. To further investigate how kindlin-3 contributes in initial platelet adhesion to collagen, we established kindlin-3 deficient HEL cell line. In contrast to parental HEL cells, PMA stimulation did not induce αIIbβ3 activation in kindlin-3 deficient HEL cells suggesting impaired inside-out signaling. The introduction of wild type kindlin-3 cDNA, but not W227X mutant, rescued αIIbβ3 activation. Conclusion: The detailed analyses by tracking single adherent platelet on collagen confirmed the role of kindlin-3 in initial step of physiological thrombus formation. Newly established kindlin-3 deficient HEL cell line is useful for further exploration of the role of kindlin-3 and inside-out signaling in platelets and expected contribution for development of new antiplatelet therapy. Disclosures Tomiyama: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Kyowa-Kirin: Honoraria.

Highly reduced penetrance in a family with a THAP1 nonsense mutation: Role of THAP1 expression?

2019 ◽  
Vol 65 ◽  
pp. 274-276 ◽  
Author(s):  
Marija Dulovic-Mahlow ◽  
Agata Gajos ◽  
Hauke Baumann ◽  
Jelena Pozojevic ◽  
Frank J. Kaiser ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Reduced Penetrance

scholarly journals Important role of melanin for fertility in the fungus Podospora anserina

2021 ◽  
Author(s):  
Valérie Gautier ◽  
Emilie Levert ◽  
Tatiana Giraud ◽  
Philippe Silar
Keyword(s):  
Nonsense Mutation ◽  
Polyketide Synthase ◽  
Podospora Anserina ◽  
Targeted Deletion ◽  
Reproductive Structures ◽  
Complete Inactivation ◽  
Mating Type Gene ◽  
Type Gene ◽  
Genetic Events

Abstract Melanins are pigments used by fungi to withstand various stresses and to strengthen vegetative and reproductive structures. In Sordariales fungi, their biosynthesis starts with a condensation step catalyzed by an evolutionary-conserved polyketide synthase. Here we show that complete Inactivation of this enzyme in the model ascomycete Podospora anserina through targeted deletion of the PaPks1 gene results in reduced female fertility, in contrast to a previously analyzed nonsense mutation in the same gene that retains full fertility. We also show the utility of PaPks1 mutants for detecting rare genetic events in P. anserina, such as parasexuality and possible fertilization and/or apomixis of nuclei devoid of mating type gene.

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