Genotype-phenotype correlations of TGFBI p.Leu509Pro, p.Leu509Arg, p.Val613Gly, and the allelic association of p.Met502Val-p.Arg555Gln mutations.

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License: CC BY 4.0
Serval ID
serval:BIB_03FE1E0DA8A2
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genotype-phenotype correlations of TGFBI p.Leu509Pro, p.Leu509Arg, p.Val613Gly, and the allelic association of p.Met502Val-p.Arg555Gln mutations.
Journal
Molecular vision
Author(s)
Niel-Butschi F., Kantelip B., Iwaszkiewicz J., Zoete V., Boimard M., Delpech M., Bourges J.L., Renard G., D'Hermies F., Pisella P.J., Hamel C., Delbosc B., Valleix S.
ISSN
1090-0535 (Electronic)
ISSN-L
1090-0535
Publication state
Published
Issued date
2011
Peer-reviewed
Oui
Volume
17
Pages
1192-1202
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural
Publication Status: ppublish
Abstract
Investigate the genotype-phenotype correlations for five TGFBI (transforming growth factor, beta-induced) mutations including one novel pathogenic variant and one complex allele affecting the fourth FAS1 domain of keratoepithelin, and their potential effects on the protein's structure.
Three unrelated families were clinically diagnosed with lattice corneal dystrophy (CD) and one with an unclassified CD of Bowman's layer. Mutations in the TGFBI gene were detected by direct sequencing, and the functional impact of each variant was predicted using in silico algorithms. Corneal phenotypes, including histological examinations, were compared with the literature data. Furthermore, molecular modeling studies of these mutations were performed.
Two distinct missense mutations affecting the same residue at position 509 of keratoepithelin: p.Leu509Pro (c.1526T>C) and p.Leu509Arg (c.1526T>G) were found to be associated with a lattice-type CD. The novel p.Val613Gly (c.1828T>G) TGFBI mutation was found in a sporadic case of an Algerian individual affected by lattice CD. Finally, the Bowman's layer CD was linked to the association in cis of the p.Met502Val and p.Arg555Gln variants, leading to the reclassification of this CD as atypical Thiel-Behnke CD. Structural modeling of these TGFBI mutations argues in favor of these mutations being responsible for instability and/or incorrect folding of keratoepithelin, predictions that are compatible with the clinical diagnoses.
Description of a novel TGFBI mutation and a complex TGFBI allele further extends the mutational spectrum of TGFBI. Moreover, we show convincing evidence that TGFBI mutations affecting Leu509 are linked to the lattice phenotype in two unrelated French families, contrasting with findings previously reported. The p.Leu509Pro was reported to be associated with both amyloid and non-amyloid aggregates, whereas p.Leu509Arg has been described as being responsible for Epithelial Basement Membrane Dystrophy (EBMD).

Keywords
Adult, Aged, 80 and over, Algeria/ethnology, Alleles, Amino Acid Sequence, Bowman Membrane/metabolism, Bowman Membrane/pathology, Corneal Dystrophies, Hereditary/classification, Corneal Dystrophies, Hereditary/epidemiology, Corneal Dystrophies, Hereditary/ethnology, Corneal Dystrophies, Hereditary/genetics, Corneal Dystrophies, Hereditary/pathology, Extracellular Matrix Proteins/genetics, Extracellular Matrix Proteins/metabolism, Female, France/epidemiology, Gene Frequency, Genetic Association Studies, Genetic Linkage, Genotype, Humans, Infant, Male, Middle Aged, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Transforming Growth Factor beta/genetics, Transforming Growth Factor beta/metabolism
Pubmed
Web of science
Create date
05/02/2018 14:53
Last modification date
20/08/2019 12:25
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