Polymorphic Corneal Amyloidosis: A Disorder Due to a Novel Mutation in the TGFB1 (BIGH3) Gene

Abstract

Abstract: : Purpose: To characterize the molecular genetic basis of an autosomal dominant form of corneal amyloidosis. Methods: The family of a patient with atypical corneal amyloidosis was investigated clinically and histopathologically. All available clinical records and slit lamp photographs were reviewed. Corneal tissue obtained at penetrating keratoplasty of several affected individuals was studied by light microscopy. DNA was isolated from blood or buccal scrapings from affected and unaffected persons over 4 generations. A mutational analysis of the TGFBI (BIGH3) gene was performed via PCR amplifications of exons 4 and 12 and subsequent nucleotide sequence analyses. Results: Examination of the family tree indicated that the corneal disorder had an autosomal dominant mode of inheritance and that all affected individuals were descendants of a German immigrant stated to have had bilateral blindness late in life. Average age of onset was 31 years, ranging from ages 17 to 41 years. Clinical symptoms at onset included dry eyes, poor night vision, and mild discomfort to changing light intensity, but no pain. Slit lamp biomicroscopy of affected individuals revealed multiple bilateral polymorphic polygonal gray and white opacities and occasional refractive lines that did not form a distinct lattice pattern. The opacities were distributed throughout the corneal stroma, especially in the posterior third. Guttata were not seen. Corneal thickness was normal. Light microscopy of the corneal tissue disclosed variably sized amyloid deposits throughout the entire thickness of the peripheral stroma, but the deposits were mostly situated posteriorly in the central cornea. The corneal endothelium and Descemet’s membrane were both unremarkable. Of the 38 family members studied twenty-two provided material for genetic analysis. Of these twenty two, the eleven affected individuals were found to have a new mutation in exon 12 of the TGFBI gene. A nucleotide substitution of cytosine for adenosine at position 1637 changed the amino acid alanine to aspartic acid at codon 546 (A546D). ). All individuals were normal in exon 4. Conclusions: A family with polymorphic corneal opacities due to deposits of amyloid in the corneal stroma was found to have a novel mutation in the TGFBI gene (A546D). The location of this mutation at codon 546 and the unusual amyloid deposition pattern may provide insight into why only certain mutated transforming growth factor beta induced proteins lead to amyloid deposition.

Keywords: pathology: human • genetics • molecular biology