Novel CHST6 Gene Mutations in 2 Unrelated Cases of Macular Corneal Dystrophy

Abstract

Purpose To investigate possible mutations in the carbohydrate sulfotransferase 6 (CHST6) gene of two unrelated cases of macular corneal dystrophy (MCD) and to report atypical stromal deposits in one of them. Methods Corneal tissues were stained with anti-sulfated keratan sulfate (KS), anti-transforming growth factor beta 1-induced protein (TGFBIp), thioflavin-T, alcian blue, and Masson trichrome. Sequencing was performed to identify potential mutations in the CHST6 gene and the fourth and twelfth exons of the TGFBI gene. Results Alcian blue staining revealed the presence of multiple subepithelial and intra-stromal mucopolysaccharide deposits, confirming the diagnosis of MCD in both cases. Immunofluorescence staining in case 1 revealed the presence of sulfated KS only in the keratocytes and select endothelial cells, consistent with MCD type IA. Preferential expression of sulfated KS was observed in keratocytes and extracellular stromal matrix in case 2, consistent with MCD type II. Atypical sub-epithelial and superficial stromal deposits were observed in case 1, which stained positively with alcian blue, eosin, Masson trichrome and thioflavin-T indicating the presence of hyaline and amyloid materials. CHST6 gene sequencing revealed two heterozygous mutations in case 1 (a p.Arg211Gln and a novel mutation of p.Arg177Gly) and a novel homozygous mutation of p.Pro186Arg in case 2. No mutations were found in exons 4 or 12 of the TGFBI gene in case 1. Conclusions Secondary hyalinosis and amyloidosis occur in a case of MCD type IA with a novel p.Arg177Gly mutation in CHST6. A novel p.Pro186Arg mutation in CHST6 is associated with MCD type II in an African American.

Keratan sulfate, a complex glycosaminoglycan with unique functional capability

“…Macular dystrophy causes deterioration of the most sensitive part of the central retina (macula), which has the highest concentration of light-sensitive cells (photoreceptors). Alterations in the degree of sulfation of KS through mutations in the CHST6 gene result in corneal opacity in macular corneal dystrophy in humans ( Edward et al 1990 ; Funderburgh et al 1990 ; El-Ashry et al 2002 , 2005 ; Liskova et al 2008 ; Dang et al 2009 ; Sultana et al 2009 ; Patel et al 2011 ).…”

“…The CHST6 gene product, corneal N -acetylglucosamine-6-sulfotransferase (C-GlcNac6ST), is important for the production of sulfated KS. Lack of activity of this enzyme results in the production of unsulfated KS, leading to a loss of transparency in the corneas of affected patients ( Edward et al 1990 ; Akama et al 2000 ; El-Ashry et al 2002 , 2005 ; Iida-Hasegawa et al 2003 ; Aldave et al 2004 ; Patel et al 2011 ).…”

Novel mutation in the CHST6 gene causes macular corneal dystrophy in a black South African family

“…We report on a consanguineous black South African family with type I MCD, which is caused by a novel E71Q mutation in CHST6 . It is the first report of MCD in a Sub-Saharan African family, although it is not the first report of MCD in an individual with African ancestry as Patel et al previously identified a novel mutation in CHST6 , which is associated with MCD type II in an African American [ 40 ].…”

A Carbohydrate Sulfotransferase‐6 (CHST6) gene mutation is associated with Macular Corneal Dystrophy in Labrador Retrievers

“…Mutations in the CHST6 gene are responsible for most cases of MCD in humans . Marked allelic heterogeneity has been documented in different populations throughout the world; more than 125 CHST6 mutations have been identified in humans with MCD . The most frequent abnormalities are missense or nonsense single nucleotide polymorphisms (SNPs) that alter a conserved part of the protein.…”