Phenotypic expression of the C282Y/Q283P compound heterozygosity in HFE and molecular modeling of the Q283P mutation effect.

Détails

ID Serval
serval:BIB_780F2E2A834F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Phenotypic expression of the C282Y/Q283P compound heterozygosity in HFE and molecular modeling of the Q283P mutation effect.
Périodique
Blood Cells, Molecules and Diseases
Auteur⸱e⸱s
Le Gac G., Dupradeau F.Y., Mura C., Jacolot S., Scotet V., Esnault G., Mercier A.Y., Rochette J., Férec C.
ISSN
1079-9796[print], 1079-9796[linking]
Statut éditorial
Publié
Date de publication
2003
Volume
30
Numéro
3
Pages
231-237
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
In Caucasians, from 4 to 35% of hereditary hemochromatosis (HH) patients carry a least one chromosome without a common assigned HFE mutation (i.e., C282Y, H63D, and S65C). We have undertaken a D-HPLC scanning of the HFE coding region in such patients in order to identify uncommon mutations liable to explain their high transferrin saturation level. Twenty HH patients from Brittany carrying at least one chromosome without an assigned mutation were selected on the basis of a transferrin saturation level with the following threshold: > or = 60% in men and > or = 50% in women, in the absence of other known causes of iron disorders. This strategy allowed us to detect a heterozygous sequence variant in exon 4 of the HFE gene from one individual who was also heterozygous for C282Y. Subsequent DNA sequencing analysis identified an adenine to cytosine transversion at position 848 which changes amino acid 283 from glutamine to proline (Q283P). Family study revealed a clear association between the C282Y/Q283P compound heterozygote genotype and the development of HH. Molecular modeling studies are in favor of a destabilizing effect of the Q283P mutation on the tertiary structure of the HFE protein. This is the first report of a natural protein variant describing the introduction of a proline in a central beta-strand position. Our approach may have practical implications in screening strategies for hereditary hemochromatosis, molecular diagnosis, and HFE structure-function relationships.
Mots-clé
DNA Mutational Analysis, Family Health, Female, France/epidemiology, Heterozygote, Histocompatibility Antigens Class I/chemistry, Histocompatibility Antigens Class I/genetics, Humans, Male, Membrane Proteins/chemistry, Membrane Proteins/genetics, Models, Molecular, Molecular Epidemiology, Mutation, Missense, Pedigree, Phenotype, Proline, Protein Structure, Tertiary, Transferrin/metabolism
Pubmed
Création de la notice
21/06/2010 10:39
Dernière modification de la notice
20/08/2019 14:34
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