Characterization of 18 new mutations in COL7A1 in recessive dystrophic epidermolysis bullosa provides evidence for distinct molecular mechanisms underlying defective anchoring fibril formation

Détails

ID Serval
serval:BIB_4E4CAF703881
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Characterization of 18 new mutations in COL7A1 in recessive dystrophic epidermolysis bullosa provides evidence for distinct molecular mechanisms underlying defective anchoring fibril formation
Périodique
American Journal of Human Genetics
Auteur(s)
Hovnanian  A., Rochat  A., Bodemer  C., Petit  E., Rivers  C. A., Prost  C., Fraitag  S., Christiano  A. M., Uitto  J., Lathrop  M., Barrandon  Y., de Prost  Y.
ISSN
0002-9297 (Print)
Statut éditorial
Publié
Date de publication
09/1997
Volume
61
Numéro
3
Pages
599-610
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Sep
Résumé
We have characterized 21 mutations in the type VII collagen gene (COL7A1) encoding the anchoring fibrils, 18 of which were not previously reported, in patients from 15 unrelated families with recessive dystrophic epidermolysis bullosa (RDEB). COL7A1 mutations in both alleles were identified by screening the 118 exons of COL7A1 and flanking intron regions. Fourteen mutations created premature termination codons (PTCs) and consisted of nonsense mutations, small insertions, deletions, and splice-site mutations. A further seven mutations predicted glycine or arginine substitutions in the collagenous domain of the molecule. Two mutations were found in more than one family reported in this study, and six of the seven missense mutations showed clustering within exons 72-74 next to the hinge region of the protein. Patients who were homozygous or compound heterozygotes for mutations leading to PTCs displayed both absence or drastic reduction of COL7A1 transcripts and undetectable type VII collagen protein in skin. In contrast, missense mutations were associated with clearly detectable COL7A1 transcripts and with normal or reduced expression of type VII collagen protein at the dermo/epidermal junction. Our results provide evidence for at least two distinct molecular mechanisms underlying defective anchoring fibril formation in RDEB: one involving PTCs leading to mRNA instability and absence of protein synthesis, the other implicating missense mutations resulting in the synthesis of type VII collagen polypeptide with decreased stability and/or altered function. Genotype-phenotype correlations suggested that the nature and location of these mutations are important determinants of the disease phenotype and showed evidence for interfamilial phenotypic variability.
Mots-clé
Alleles Arginine/genetics Basement Membrane Codon, Terminator/genetics Collagen/analysis/*genetics Epidermolysis Bullosa Dystrophica/*genetics/pathology Gene Expression Genes, Recessive/genetics Genotype Glycine/genetics Humans Keratinocytes Mutation/*genetics RNA Splicing/genetics RNA, Messenger/genetics Skin/chemistry/*pathology/ultrastructure
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/01/2008 9:41
Dernière modification de la notice
20/08/2019 15:03
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