Novel mutations in the carbohydrate sulfotransferase gene (CHST6) in American patients with macular corneal dystrophy

Aldave, Anthony J.; Yellore, Vivek S.; Thonar, Eugene J-M.A.; Udar, Nitin; Warren, John F; Yoon, Michael K.; Cohen, Elisabeth J.; Rapuano, Christopher J.; Laibson, Peter R.; Margolis, Todd P.; Small, Kent W.

doi:10.1016/j.ajo.2003.09.036

Cited by 37 publications

(26 citation statements)

References 24 publications

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“…The CHST6 gene has been reported to be involved in the pathogenesis of macular corneal dystrophy by affecting the synthesis of keratan sulfate [5][6][7][8][9][10][11][12][13][14]. Each of the novel coding region mutations detected here is predicted to cause significant changes in the encoded protein C-GlcNAc6ST.…”

Section: Discussionmentioning

confidence: 94%

“…This substitution was predicted to be a polymorphism in previous reports which found that this amino acid change is present in the normal population with an allelic frequency of 6.3% [13].…”

Section: Single-nucleotide Polymorphismmentioning

confidence: 86%

“…Another previously unreported missense mutation results in an amino acid side chain substitution on codon 173. Recently Aldave et al [13] demonstrated that codon 173 is a conserved region. Therefore this mutation affecting conserved residues of the enzyme may destabilize an essential structure or impede gene function in an as yet unknown manner.…”

Section: Discussionmentioning

confidence: 99%

“…Various mutation analyses of the CHST6 gene have revealed several missense and nonsense mutations that lead to inactivation of CHST6 within the coding region in patients with MCD type I. MCD type II patients, who have normal keratan sulfate levels in their serum, may additionally show large deletions and replacements caused by homologous recombination in the upstream region of the CHST6 gene, although CHST6 mutations have been described in MCD type II patients [6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Macular corneal dystrophy: mutational spectrum in German patients, novel mutations and therapeutic options

Gruenauer-Kloevekorn

Braeutigam

Heinritz

et al. 2008

Graefes Arch Clin Exp Ophthalmol

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Section: Discussionmentioning

confidence: 94%

Section: Single-nucleotide Polymorphismmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Macular corneal dystrophy: mutational spectrum in German patients, novel mutations and therapeutic options

Gruenauer-Kloevekorn

Braeutigam

Heinritz

et al. 2008

Graefes Arch Clin Exp Ophthalmol

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“…Thus, in mouse, Chst5 is the biologically equivalent gene for CHST6 in humans, and a knockout of Chst5 in mouse represents a lack of functional CHST6 in humans. CHST6 mutations are found in the genomes of macular corneal dystrophy patients throughout the world (10,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50), and in the few human corneas that have been examined postoperatively by x-ray fiber diffraction, collagen fibrils are, on average, normal in diameter but are more closely spaced (51). We contend that collagen matrix compaction in the Chst5-null mouse is a direct consequence of KS undersulfation.…”

Section: Discussionmentioning

confidence: 99%

Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6- O -sulfotransferase

Hayashida

Akama

Beecher

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Matrix assembly and homeostasis in collagen-rich tissues are mediated by interactions with proteoglycans (PGs) substituted with sulfated glycosaminoglycans (GAGs). The major GAG in cornea is keratan sulfate (KS), which is N-linked to one of three PG core proteins. To ascertain the importance of the carbohydrate chain sulfation step in KS functionality, we generated a strain of mice with a targeted gene deletion in Chst5, which encodes an N-acetylglucosamine-6-O-sulfotransferase that is integral to the sulfation of KS chains. Corneas of homozygous mutants were significantly thinner than those of WT or heterozygous mice. They lacked high-sulfated KS, but contained the core protein of the major corneal KSPG, lumican. Histochemically stained KSPGs coassociated with fibrillar collagen in WT corneas, but were not identified in the Chst5-null tissue. Conversely, abnormally large chondroitin sulfate͞dermatan sulfate PG complexes were abundant throughout the Chst5-deficient cornea, indicating an alteration of controlled PG production in the mutant cornea. The corneal stroma of the Chst5-null mouse exhibited widespread structural alterations in collagen fibrillar architecture, including decreased interfibrillar spacing and a more spatially disorganized collagen array. The enzymatic sulfation of KS GAG chains is thus identified as a key requirement for PG biosynthesis and collagen matrix organization.collagen ͉ glycosaminoglycans ͉ proteoglycans G lycosaminoglycans (GAGs) substituted on proteoglycans (PGs) are influential in defining collagen fibrillar architecture in a wide range of connective tissue matrices. Keratan sulfate (KS) is an important constituent of several collagen-rich tissues and is the major GAG in cornea where it is N-linked to asparagine residues in one of three PG core proteins: lumican (1), keratocan (2), and mimecan͞osteoglycin (3). Human corneal GlcNAc 6-O-sulfotransferase (also known as human GlcNAc6ST-5 and GST4␤) is the responsible enzyme for the synthesis of high-sulfated KS via the transfer of sulfate onto the GlcNAc 6-O position of the KS backbone (4).Fairly compelling evidence exists for a regulatory role for KSPGs in the maintenance of corneal matrix structure in a number of species. The avian cornea in ovo, for example, synthesizes an unsulfated form of KS midway through development when it is structurally disorganized and transmits relatively little light, but switches to produce a sulfated KS GAG as it becomes transparent and attains a more well ordered collagen fibrillar ultrastructure (5, 6). KS sulfation patterns are also altered in opaque, structurally disorganized corneal scar tissue in rabbits (7,8) and in cloudy human corneas with the inherited disease, macular corneal dystrophy (9), which is caused by mutations in CHST6, a gene encoding human corneal GlcNAc 6-O-sulfotransferase (10).Hybrid type I͞V collagen fibrils are the cornea's main nonspecular light-scattering elements and are formed into wide, interweaving belts or lamellae that lie approximately in the tissue plane (11). Wit...

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Elucidating the Molecular Genetic Basis of the Corneal Dystrophies

Aldave¹

2007

Arch Ophthalmol

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Novel mutations in the carbohydrate sulfotransferase gene (CHST6) in American patients with macular corneal dystrophy

Cited by 37 publications

References 24 publications

Macular corneal dystrophy: mutational spectrum in German patients, novel mutations and therapeutic options

Macular corneal dystrophy: mutational spectrum in German patients, novel mutations and therapeutic options

Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6- O -sulfotransferase

Elucidating the Molecular Genetic Basis of the Corneal Dystrophies

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