The molecular genetics of the corneal dystrophies - current status

Abstract

The pertinent literature on inherited corneal diseases is reviewed in terms of the chromosomal localization and identification of the responsible genes. Disorders affecting the cornea have been mapped to human chromosome 1 (central crystalline corneal dystrophy, familial subepithelial corneal amyloidosis, early onset Fuchs dystrophy, posterior polymorphous corneal dystrophy), chromosome 4 (Bietti marginal crystalline dystrophy), chromosome 5 (lattice dystrophy types 1 and IIIA, granular corneal dystrophy types 1, 2 and 3, Thiel-Behnke corneal dystrophy), chromosome 9 (lattice dystrophy type II), chromosome 10 (Thiel-Behnke corneal dystrophy), chromosome 12 (Meesmann dystrophy), chromosome 16 (macular corneal dystrophy, fish eye disease, LCAT disease, tyrosinemia type II), chromosome 17 (Meesmann dystrophy, Stocker-Holt dystrophy), chromosome 20 (congenital hereditary endothelial corneal dystrophy types I and II, posterior polymorphous corneal dystrophy), chromosome 21 (autosomal dominant keratoconus) and the X chromosome (cornea verticillata, cornea farinata, deep filiform corneal dystrophy, keratosis follicularis spinulosa decalvans, Lisch corneal dystrophy). Mutations in nine genes (ARSC1, CHST6, COL8A2, GLA, GSN, KRT3, KRT12, M1S1and TGFBI [BIGH3]) account for some of the corneal diseases and three of them are associated with amyloid deposition in the cornea (GSN, M1S1, TGFBI) including most of the lattice corneal dystrophies (LCDs) [LCD types I, IA, II, IIIA, IIIB, IV, V, VI and VII] recognized by their lattice pattern of linear opacities. Genetic studies on inherited diseases affecting the cornea have provided insight into some of these disorders at a basic molecular level and it has become recognized that distinct clinicopathologic phenotypes can result from specific mutations in a particular gene, as well as some different mutations in the same gene. A molecular genetic understanding of inherited corneal diseases is leading to a better appreciation of the pathogenesis of these conditions and this knowledge has made it imperative to revise the classification of inherited corneal diseases.

Q455V mutation in COL8A2 is associated with Fuchs' corneal dystrophy in Korean patients

“…6,7 Although rare, there is also an early onset form of this disease. 2,7,8 Although its pathogenesis has not been clearly elucidated, FECD is known to be an autosomal dominant disease with high penetrance that develops independently from systemic or environmental factors. [7][8][9] Therefore, understanding the genetic component of this disease is critical for the development of future therapies and preventative care.…”

Enzymes Responsible for Synthesis of Corneal Keratan Sulfate Glycosaminoglycans

“…Observations that macular corneal dystrophy patients with CGn6ST mutations develop corneal opacities (21) and that mice lacking the orthologous sulfotransferase display corneal thinning with abnormalities in corneal extracellular matrix structure (9) indicate important roles for KS GAG sulfation in the function and maintenance of the cornea. However, unlike KS sulfation, mechanisms underlying KS GAG chain elongation are poorly understood.…”

First Genetic Analysis of Lattice Corneal Dystrophy Type I in a Family from Bulgaria

“…At least 15 different mutations in TGFBI, accompanied by amyloid deposition in the cornea, have been identified in families with diff e rent clinical variants of lattice c o rneal dystrophy (LCD): R124C, R124H, L518P, P501T, L527R, A546T, L569R, A622H, H620R, H626R, L527R, A 5 4 6 T, A546D, H620R, 9-bp insertion at nt 1885-1886, and missense at nt 1887. Therefore, due to such genetic h e t e ro g e n e i t y, in order to assess a final diagnosis it is strictly necessary to identify which specific mutations are carried by the patient (1)(2)(3)(4)(5).…”

“…Based on phenotypic and clinical analysis, a large number of LCD subtypes have been identified so far in many different geographic areas (1). Recently, at least some LCDs have been considered a result of mutations in the ?ig-h3 gene, located on chromosome V and encoding for the adhesion molecule keratoepithelin (2).…”