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

Niel-Butschi F, Kantelip B, Iwaszkiewicz J, Zoete V, Boimard M, Delpech M, Bourges JL, Renard G, D'Hermies F, Pisella PJ, Hamel C, Delbosc B, Valleix S - Mol. Vis. (2011)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Inserm, U1016, Institut Cochin, CNRS, UMR 8104, Université Paris-Descartes, Paris, France.

ABSTRACT

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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).

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Case D at 80 years of age. A: Representative images of corneal opacities (arrowhead) seen in the right eye of case D, at 80 years of age. B: Electropherograms around the codon 613 in exon 14 of the TGFBI gene. The patient is heterozygous for a novel mutation, thymine to guanine substitution at position 1828 (c. 1828T>G), causing the p.Val613Gly amino acid exchange. C: Partial amino acid sequence alignment of keratoepithelin with ten of its orthologs. The boxes indicate valine at position 613 in the human protein.
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f4: Case D at 80 years of age. A: Representative images of corneal opacities (arrowhead) seen in the right eye of case D, at 80 years of age. B: Electropherograms around the codon 613 in exon 14 of the TGFBI gene. The patient is heterozygous for a novel mutation, thymine to guanine substitution at position 1828 (c. 1828T>G), causing the p.Val613Gly amino acid exchange. C: Partial amino acid sequence alignment of keratoepithelin with ten of its orthologs. The boxes indicate valine at position 613 in the human protein.

Mentions: The patient was an Algerian male, born in 1925, who was referred, at the age of 80, for evaluation of bilateral corneal dystrophy to the Hotel-Dieu Hospital in Paris (Figure 4A). A corneal graft of the right eye was performed and on histological examination numerous findings suggested a lattice type corneal dystrophy. The majority of the cornea epithelium was abraded; the Bowman's layer was slightly wrinkled at the anterior corneal surface. The stroma appeared slightly thickened and contained eosinophilic deposits. These aggregates did not take up Masson's trichrome stain but showed positive staining with Congo red and thioflavin-T. This patient has 12 children but little clinical information is available on them, except for one child born in 1954, who has been monitored in Algeria and who has exhibited small dots and a star-shaped opacity.


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

Niel-Butschi F, Kantelip B, Iwaszkiewicz J, Zoete V, Boimard M, Delpech M, Bourges JL, Renard G, D'Hermies F, Pisella PJ, Hamel C, Delbosc B, Valleix S - Mol. Vis. (2011)

Case D at 80 years of age. A: Representative images of corneal opacities (arrowhead) seen in the right eye of case D, at 80 years of age. B: Electropherograms around the codon 613 in exon 14 of the TGFBI gene. The patient is heterozygous for a novel mutation, thymine to guanine substitution at position 1828 (c. 1828T>G), causing the p.Val613Gly amino acid exchange. C: Partial amino acid sequence alignment of keratoepithelin with ten of its orthologs. The boxes indicate valine at position 613 in the human protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3102024&req=5

f4: Case D at 80 years of age. A: Representative images of corneal opacities (arrowhead) seen in the right eye of case D, at 80 years of age. B: Electropherograms around the codon 613 in exon 14 of the TGFBI gene. The patient is heterozygous for a novel mutation, thymine to guanine substitution at position 1828 (c. 1828T>G), causing the p.Val613Gly amino acid exchange. C: Partial amino acid sequence alignment of keratoepithelin with ten of its orthologs. The boxes indicate valine at position 613 in the human protein.
Mentions: The patient was an Algerian male, born in 1925, who was referred, at the age of 80, for evaluation of bilateral corneal dystrophy to the Hotel-Dieu Hospital in Paris (Figure 4A). A corneal graft of the right eye was performed and on histological examination numerous findings suggested a lattice type corneal dystrophy. The majority of the cornea epithelium was abraded; the Bowman's layer was slightly wrinkled at the anterior corneal surface. The stroma appeared slightly thickened and contained eosinophilic deposits. These aggregates did not take up Masson's trichrome stain but showed positive staining with Congo red and thioflavin-T. This patient has 12 children but little clinical information is available on them, except for one child born in 1954, who has been monitored in Algeria and who has exhibited small dots and a star-shaped opacity.

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Inserm, U1016, Institut Cochin, CNRS, UMR 8104, Université Paris-Descartes, Paris, France.

ABSTRACT

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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).

Show MeSH
Related in: MedlinePlus