Abstract
Purpose::
Corneal dystrophies (CDs) are hereditary conditions characterized by the progressive accumulation of deposits on different layers of the cornea. They are clinically and genetically heterogeneous disorders that initiate in the first decades of life, affect the central cornea, and are not associated with inflammation. A group of autosomal dominant (AD) CDs arises from mutations in the 5q31-located transforming growth factor-ß induced (TGFBI) gene. Approximately 30 distinct TGFBI mutations have been demonstrated in four AD Bowman's layer/stromal CDs: granular CD type I, granular CD type II or Avellino type, granular CD type III (Reis-Bücklers dystrophy), and Lattice CD of types I, IIIA, I/IIIA, IIIB, and IV. Recently, a distinct, autosomal dominant, progressive form of corneal amyloidosis characterized by the presence of refractile polymorphic corneal opacities, was described. This disease, termed polymorphic corneal amyloidosis, was demonstrated to be caused by a TGFBI A546D mutation. We report a new family carrying the A546D and exhibiting important phenotypic differences with respect to the original polymorphic corneal amyloidosis family.
Methods::
A complete ophthalmological examination was performed in 10 individuals of a Mexican family in which autosomal dominant transmission of a CD was observed. Genetic analyses included TGFBI gene PCR amplification, and automated nucleotidic sequencing of exons 4, 11, 12, 13, and 14 from genomic DNA of each participating subject.
Results::
The onset of the disease was in the third decade of life. CD phenotype in this family was characterized by multiple bilateral polymorphic opacities in the central part of the cornea combined with a conspicuous lattice pattern. Multiple thick lattice lines were also present in the corneal periphery. TGFBI analysis revealed a heterozygous point mutation at exon 12, predicting an A546D missense mutation in affected individuals.
Conclusions::
This is the second family in which a TGFBI A546D heterozygous mutation has been described. The observed phenotype sharply contrasts with that observed in a previous family carrying the A546D mutation and which exhibited "chipped ice"-appearing corneal opacities with occasional filamentous lines that did not form a distinct lattice pattern. Our results indicate that important interfamilial phenotypic differences can be associated to the TGFBI A546D mutation and suggest that this mutation causes an atypical variant of granular/lattice corneal dystrophy.
Keywords: cornea: clinical science • genetics • mutations