A New Model of Hereditary Spherocytosis Demonstrates Profound Homeostatic Compensation in Severely Anemic Mice.
Notice bibliographique
Résumé
Abstract As part of a concerted program to generate new models of human disease we have generated multiple heritable mutant mouse strains using ethylnitrosourea (ENU) random mutagenesis combined with a dominant blood screen. Here we describe a mutant strain with dominantly-inherited red blood cell (RBC) low mean corpuscular volume. Preliminary phenotypic analysis of affected mice demonstrated spherical RBC morphology, increased osmotic fragility, mild reticulocytosis and a reduction in circulating lifetime - features characteristic of human hereditary spherocytosis. Gene mapping revealed the causative point mutation to be in the mouse ankyrin-1 gene (Ank1) locus at exon 26 - a G to T transversion causing substitution of a glutamate codon with a premature stop (Ank1*895). The resulting gene product is a truncated ankyrin-1 protein (terminating at amino acid 894) consisting primarily of the N-terminal band 3-binding domain without a functional ZU5 domain (spectrin-binding) or regulatory/death domain (Fig.1). The Ank1*895 allele results in a hypomorph such that stably-expressed protein isolated from RBC ghost preparations is undetectable by Coomasie stain and only barely detectable by Western. Our ENU-generated mutation is distinct from the spontaneous mutation identified in the normoblastosis (nb) mouse (Peters et al. 1991. J. Cell Biol; Birkenmeier et al. 2003. Hematol J.) which yields a functional protein product with intact band 3- and spectrin-binding domains (Fig.1). Figure 1. Schematic representation of mouse ankyrin-1 peptide showing sites of truncation products encoded by the ENU-generated nonsense mutation Ank1*895 (Glu → stop) and the normoblastosis (nb) mouse (Ank1nb). While the phenotype of the heterozygous (Ank1*895/+) mutant line on the C3H background is mild, intercross breeding of mutant mice did not yield pups homozygous for the mutant allele - suggesting an embryonic lethal phenotype. Surprisingly, when the C3H-Ank1*895 line was bred with the SvImJ/129 strain we were able to obtain viable homozygous Ank1*895/*895 offspring from intercross of the Ank1*895/+ 129xC3H hybrid mutant line. Homozygous Ank1*895 mice were obtained at low frequency and displayed a severe phenotype with remarkable splenomegaly. In this study we have generated a novel mouse model of hereditary spherocytosis and examined the compensatory mechanisms that permit the survival of homozygous Ank1*895 mice from embryo to adults. In addition, we determined the stability of Ank1*895 protein in homozygous mice and its effect on the assembly of RBC membrane structural complexes in the absence of full-length ankyrin-1. MRH and SM are fellows of the CIHR/HSFC Strategic Training Program in Transfusion Science at the UBC Centre for Blood Research (CBR). KMM is a Michael Smith Foundation for Health Research Scholar and CBR member. This study was supported by a group operating grant from the CIHR (FRN 74611) and fellowships from the Heart & Stroke/Richard Lewar Centre of Excellence. Figure 1. Schematic representation of mouse ankyrin-1 peptide showing sites of truncation products encoded by the ENU-generated nonsense mutation Ank1*895 (Glu → stop) and the normoblastosis (nb) mouse (Ank1nb). While the phenotype of the heterozygous (Ank1*895/+) mutant line on the C3H background is mild, intercross breeding of mutant mice did not yield pups homozygous for the mutant allele - suggesting an embryonic lethal phenotype. Surprisingly, when the C3H-Ank1*895 line was bred with the SvImJ/129 strain we were able to obtain viable homozygous Ank1*895/*895 offspring from intercross of the Ank1*895/+ 129xC3H hybrid mutant line. Homozygous Ank1*895 mice were obtained at low frequency and displayed a severe phenotype with remarkable splenomegaly. In this study we have generated a novel mouse model of hereditary spherocytosis and examined the compensatory mechanisms that permit the survival of homozygous Ank1*895 mice from embryo to adults. In addition, we determined the stability of Ank1*895 protein in homozygous mice and its effect on the assembly of RBC membrane structural complexes in the absence of full-length ankyrin-1. MRH and SM are fellows of the CIHR/HSFC Strategic Training Program in Transfusion Science at the UBC Centre for Blood Research (CBR). KMM is a Michael Smith Foundation for Health Research Scholar and CBR member. This study was supported by a group operating grant from the CIHR (FRN 74611) and fellowships from the Heart & Stroke/Richard Lewar Centre of Excellence.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».