New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to β-adrenergic stimulation-induced cardiac fibrosis.
Abnormalities, Multiple
/ diagnosis
Adrenergic beta-Agonists
Alleles
Animals
Cardiomegaly
/ diagnosis
Disease Models, Animal
Echocardiography
Female
Fibrosis
Genetic Association Studies
Genetic Loci
Germ-Line Mutation
Heart Function Tests
Immunohistochemistry
Kaplan-Meier Estimate
Male
Mice
Mice, Transgenic
Mutation
Noonan Syndrome
/ complications
Phenotype
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
ras Proteins
/ genetics
AKT
Cardiac fibrosis
Cardiac hypertrophy
Noonan syndrome
RIT1
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Apr 2019
Apr 2019
Historique:
received:
10
12
2018
revised:
27
02
2019
accepted:
06
03
2019
pubmed:
23
3
2019
medline:
21
8
2019
entrez:
23
3
2019
Statut:
ppublish
Résumé
Noonan syndrome (NS) is a genetic disorder characterized by short stature, a distinctive facial appearance, and heart defects. We recently discovered a novel NS gene, RIT1, which is a member of the RAS subfamily of small GTPases. NS patients with RIT1 mutations have a high incidence of hypertrophic cardiomyopathy and edematous phenotype, but the specific role of RIT1 remains unclear. To investigate how germline RIT1 mutations cause NS, we generated knock-in mice that carried a NS-associated Rit1 A57G mutation (Rit1 Rit1 The A57G mutation in Rit1 causes cardiac hypertrophy, fibrosis and other NS-associated features. Biochemical analysis indicates that the AKT signaling pathway might be related to downstream signaling in the RIT1 A57G mutant at a developmental stage and under β-adrenergic stimulation in the heart. FUND: The Grants-in-Aid were provided by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science KAKENHI Grant.
Sections du résumé
BACKGROUND
BACKGROUND
Noonan syndrome (NS) is a genetic disorder characterized by short stature, a distinctive facial appearance, and heart defects. We recently discovered a novel NS gene, RIT1, which is a member of the RAS subfamily of small GTPases. NS patients with RIT1 mutations have a high incidence of hypertrophic cardiomyopathy and edematous phenotype, but the specific role of RIT1 remains unclear.
METHODS
METHODS
To investigate how germline RIT1 mutations cause NS, we generated knock-in mice that carried a NS-associated Rit1 A57G mutation (Rit1
FINDINGS
RESULTS
Rit1
INTERPRETATION
CONCLUSIONS
The A57G mutation in Rit1 causes cardiac hypertrophy, fibrosis and other NS-associated features. Biochemical analysis indicates that the AKT signaling pathway might be related to downstream signaling in the RIT1 A57G mutant at a developmental stage and under β-adrenergic stimulation in the heart. FUND: The Grants-in-Aid were provided by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science KAKENHI Grant.
Identifiants
pubmed: 30898653
pii: S2352-3964(19)30154-9
doi: 10.1016/j.ebiom.2019.03.014
pmc: PMC6491386
pii:
doi:
Substances chimiques
Adrenergic beta-Agonists
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
RIT1 protein, human
EC 3.6.1.-
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Pagination
43-53Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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