Quebec Platelet Disorder Is Caused by a Cis-Acting Mutation near the Plasminogen Activator Gene (PLAU) That Increases PLAU Transcription by Megakaryocytes.
Notice bibliographique
Résumé
Abstract Quebec platelet disorder (QPD) is an autosomal dominant disorder, with high penetrance, that is associated with increased risks for bleeding and a gain-of-function defect in fibrinolysis. Its hallmark feature is a markedly increased platelet content of urokinase plasminogen activator (uPA), without systemic fibrinolysis or increased uPA in plasma or urine. Recent studies of 28 affected and 110 unaffected individuals from the QPD pedigree linked the disorder to a 2 megabase region on chromosome 10q containing PLAU, the uPA gene (J Thromb Haemost2007;5: Suppl.2: O-S-021). This led us to investigate if QPD was caused by a mutation within or near PLAU, and if the disorder increased transcription of one or both PLAU alleles in megakaryocytes. Single nucleotide polymorphism (SNP) arrays (Illumina 1M BeadChip), Southern blotting, and sequencing were used to investigate genetic changes within the linked region (n= 1–3 QPD and 1–3 control individuals). To assess expression of PLAU alleles, heterozygous individuals (n= 4 QPD, 5 controls) were evaluated by a quantitative Taqman® 5’ nuclease assay for SNP rs4065 alleles (T/C; T allele inherited by all affected individuals) using reverse transcribed mRNA from platelets, CD 34+ hematopoietic progenitors, and saliva. Quantitative RTPCR of QPD platelet mRNA was used to determine if the disorder increased expression of the genes flanking PLAU on chromosome 10 which encode vinculin (VCL) and calmodulin-dependent protein kinase IIγ (CAMK2G). No abnormalities near PLAU were detected in QPD subjects evaluated by Southern blotting. No insertions or duplications were detected by SNP array analysis, which provided data on 80 markers over the region of chromosome 10 nearest to PLAU. Analysis of a rare SNP, 13.7 kb upstream of PLAU, that was present in 28/28 with QPD and 4/110 unaffected family members, confirmed linkage of the region near PLAU to QPD (LOD score +11.8). Sequence analyses confirmed a common QPD haplotype for the linked region and excluded the possibility that QPD resulted from mutations in the promoter or in the 11 exons and 10 introns of PLAU. No mutations were found by extended sequencing of the regions extending 20 kb upstream and 1 kb downstream of PLAU which includes all of its known regulatory elements and the 3’ message instability region. Analysis of SNP rs4065 in PLAU indicated that there was a marked increased expression of the linked T allele in QPD platelets (>150-fold increase; p = <0.016 compared to controls; confirmed by sequencing) but minimal (2–4 fold) increased expression of this allele in QPD CD 34+ cells and saliva cells. Unlike PLAU, VCL and CAMK2G were not overexpressed in QPD platelets. Our data indicate that inheritance of QPD results from a cis-regulatory defect, outside the known regulatory elements of PLAU, that generates profibrinolytic platelets by markedly increasing transcription of the linked PLAU allele during megakaryopoiesis, without increasing PLAU transcription by non-hematopoietic saliva cells.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,011 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».