Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location
| Autor: | Catherine Benoist, Jacky Bonaventure, Sandra Aresta, Vincent El Ghouzzi, Arnold Munnich, Laurence Legeai-Mallet, Jean de Gunzburg |
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| Přispěvatelé: | Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Transduction du signal et oncogénèse, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Joseph Louis LAGRANGE (LAGRANGE), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2000 |
| Předmět: |
Genotype
[SDV]Life Sciences [q-bio] Nonsense mutation [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Protein degradation medicine.disease_cause Craniosynostoses 03 medical and health sciences Twist transcription factor 0302 clinical medicine Two-Hybrid System Techniques Genetics medicine Animals Missense mutation Nuclear protein Molecular Biology Genetics (clinical) 030304 developmental biology Cell Nucleus [SDV.GEN]Life Sciences [q-bio]/Genetics 0303 health sciences Mutation Hydrolysis Twist-Related Protein 1 Protein turnover Nuclear Proteins General Medicine medicine.disease Cell biology Phenotype [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics 030220 oncology & carcinogenesis COS Cells Saethre–Chotzen syndrome Transcription Factors |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2000, 9 (5), pp.813-819. ⟨10.1093/hmg/9.5.813⟩ Human Molecular Genetics, 2000, 9 (5), pp.813-819. ⟨10.1093/hmg/9.5.813⟩ |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/9.5.813 |
| Popis: | International audience; H-TWIST belongs to the family of basic helix-loop-helix (bHLH) transcription factors known to exert their activity through dimer formation. We have demonstrated recently that mutations in H-TWIST account for Saethre-Chotzen syndrome (SCS), an autosomal dominant craniosynostosis syndrome characterized by premature fusion of coronal sutures and limb abnormalities of variable severity. Although insertions, deletions, nonsense and missense mutations have been identified, no genotype-phenotype correlation could be found, suggesting that the gene alterations lead to a loss of protein function irrespective of the mutation. To assess this hypothesis, we studied stability, dimerization capacities and subcellular distribution of three types of TWIST mutant. Here, we show that: (i) nonsense mutations resulted in truncated protein instability; (ii) missense mutations involving the helical domains led to a complete loss of H-TWIST heterodimerization with the E12 bHLH protein in the two-hybrid system and dramatically altered the ability of the TWIST protein to localize in the nucleus of COS-transfected cells; and (iii) in-frame insertion or missense mutations within the loop significantly altered dimer formation but not the nuclear location of the protein. We conclude that at least two distinct mechanisms account for loss of TWIST protein function in SCS patients, namely protein degradation and subcellular mislocalization. |
| Databáze: | OpenAIRE |
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