Clinical and Genetic Aspects of the TGFBI-associated Corneal Dystrophies

Lakshminarayanan, Rajamani; Chaurasia, Shyam S.; Venkatraman, Anandalakshmi; Chai, Shu-Ming; Murugan, Elavazhagan; Vithana, Eranga N.; Beuerman, Roger W.; Mehta, Jodhbir S.

doi:10.1016/j.jtos.2013.12.002

Cited by 62 publications

(72 citation statements)

References 108 publications

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“…In addition, CLU is markedly elevated in Fuchs' Endothelial Corneal Dystrophy (FECD), the most common cause of corneal endothelial dysfunction [108][109][110]. The disease is characterized by accumulation of extracellular collagenous deposits called "guttae" posterior to Descemet's membrane, the specialized extracellular matrix that backs the corneal endothelium [111]. Earlyonset FECD has been linked genetically to a mutation in the COL8A2 (2 chain of collagen VIII) gene encoding a component of Descemet's membrane [112].…”

Section: Corneal Dystrophies -This Is a Group Of Inherited Disorders mentioning

confidence: 99%

Clusterin in the eye: An old dog with new tricks at the ocular surface

Fini

Bauskar

Jeong

et al. 2016

Experimental Eye Research

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, M. R. (2016). Clusterin in the eye: an old dog with new tricks at the ocular surface. Experimental Eye Research, Clusterin in the eye: an old dog with new tricks at the ocular surface AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had been demonstrated throughout the body, including in the eye. Its homeostatic activities in proteostasis, cytoprotection, and anti-inflammation have been well documented, however its roles in health and disease are still not well understood. CLU is prominent at fluid-tissue interfaces, and in 1996 it was demonstrated to be the most highly expressed transcript in the human cornea, the protein product being localized to the apical layers of the mucosal epithelia of the cornea and conjunctiva. CLU protein is also present in human tears. Using a preclinical mouse model for desiccating stress that mimics human dry eye disease, the authors recently demonstrated that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration in the tears. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to LGALS3 (galectin-3), a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. CLU depletion from the ocular surface epithelia is seen in a variety of inflammatory conditions in humans and mice that lead to squamous metaplasia and a keratinized epithelium. This suggests that CLU might have a specific role in maintaining mucosal epithelial differentiation, an idea that can now be tested using the mouse model for desiccating stress. Most excitingly, the new findings suggest that CLU could serve as a novel biotherapeutic for dry eye disease. Competing Interests: US patent 9,241,974 B2 entitled "Clusterin pharmaceuticals and treatment methods using the same" (inventors: MEF and SJ), assigned to the University of Southern California, is connected with this work. MEF holds a management position with Proteris Biotech, Inc., Pasadena, CA, which is developing Protearin for dry eye based on clusterin. MRW declares that he has no competing interests. Page 3 of 65 AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had bee...

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Section: Corneal Dystrophies -This Is a Group Of Inherited Disorders mentioning

confidence: 99%

Clusterin in the eye: An old dog with new tricks at the ocular surface

Fini

Bauskar

Jeong

et al. 2016

Experimental Eye Research

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“…The amino acid most commonly affected by mutations in TGFBI is p.Arg124, upstream of the FAS1 domain repeats. 37 Intriguingly, different mutations affecting this site can lead to either amyloidogenic deposits causing LCD1 (p.Arg124Cys, 372 reported cases) or nonamyloidogenic deposits causing RBCD (p.Arg124Leu, 63 reported cases). [37][38][39] Mutations involving p.Arg555 are also relatively common, typically causing either GCD1 (p.Arg555Trp, 375 reported cases) or TBCD (p.Arg555Gln, 66 reported cases).…”

Section: Tgfbi-associated Corneal Dystrophiesmentioning

confidence: 99%

“…37 Intriguingly, different mutations affecting this site can lead to either amyloidogenic deposits causing LCD1 (p.Arg124Cys, 372 reported cases) or nonamyloidogenic deposits causing RBCD (p.Arg124Leu, 63 reported cases). [37][38][39] Mutations involving p.Arg555 are also relatively common, typically causing either GCD1 (p.Arg555Trp, 375 reported cases) or TBCD (p.Arg555Gln, 66 reported cases). 37 One example where the genotype-phenotype correlation is not so clear is the p.His626Pro mutation, which has been reported with an overlapping phenotype of RBCD and TBCD.…”

Section: Tgfbi-associated Corneal Dystrophiesmentioning

confidence: 99%

The Genetics and Pathophysiology of IC3D Category 1 Corneal Dystrophies

Oliver

Vincent

2016

Asia-Pacific Journal of Ophthalmology

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Corneal dystrophies are a group of inherited disorders affecting the cornea, many of which lead to visual impairment. The International Committee for Classification of Corneal Dystrophies has established criteria to clarify the status of the various corneal dystrophies, which include the knowledge of the underlying genetics. In this review, we discuss the International Committee for Classification of Corneal Dystrophies category 1 (second edition) corneal dystrophies, for which a clear genetic link has been established. We highlight the various mechanisms underlying corneal dystrophy pathology, including structural disorganization, instability or maladhesion, aberrant protein stability and deposition, abnormal cellular proliferation or apoptosis, and dysfunction of normal enzymatic processes. Understanding these genetic mechanisms is essential for designing targets for therapeutic intervention, especially in the age of gene therapy and gene editing.

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“…Mutations of the carbohydrate sulfotransferase 6 and transforming growth factor β induced (TGFBI) gene have been reported to cause macular corneal dystrophy and corneal disease (4). Currently, LCDI has been associated with a large number of missense mutations with genotype-phenotype correlations in the TGFBI gene, and the International Committee for Classification of Corneal Dystrophies categorized it as LCD-TGFBI type (3,7).…”

Section: Introductionmentioning

confidence: 99%

“…So far, ~50 different mutations causing LCD have been identified in the TGFBI gene (www.hgmd.org). The TGFBI mutation spectrum and their clinical consequences have been investigated in patients with LCDI in different ethnic populations (2,7,(9)(10)(11)(12)(13). For example, the p.Arg124Cys mutation is reported to be associated with the LCDI phenotype in Greek, Japanese, Bangladeshi and Chinese patients (14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor β induced mutation-associated phenotype in a Chinese family exhibiting lattice corneal dystrophy

Guo

et al. 2017

Biomedical Reports

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Abstract. Lattice corneal dystrophy type I (LCDI) is associated with a large number of missense mutations in the transforming growth factor β induced (TGFBI) gene. The aim of the present study was to analyze TGFBI mutation in a Chinese family with LCDI, and to describe the clinical features and phenotype-genotype correlation within this family. Three generations of this family with LCDI were enrolled in the current study. Complete ophthalmic examinations were performed on all family members and mutation screenings of the coding regions of TGFBI were analyzed using a direct sequencing method. All family members underwent slit-lamp examination, and two patients and one of normal members in the family were evaluated by laser scanning in vivo confocal microscopy. A single heterozygous c.370C>T (p.R124C) mutation was identified in exon 4 of the TGFBI gene in five affected individuals, but not in the other family members and 400 normal control subjects. The affected members exhibited similar clinical features of LCDI, except that patient III:5 presented with mild symptoms. Confocal microscopy in vivo examination demonstrated that the proband (II:2) and his affected niece (III:4) had disruptions in multiple corneal layers, including the basal epithelial cells, stroma cells and Bowman's membrane. Thus, the R124C mutation in the TGFBI gene was identified in a Chinese family with LCDI. These results characterized the clinical features and revealed a genotype-associated phenotype in this family, which may contribute to understanding the pathogenesis of LCDI.

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Clinical and Genetic Aspects of the TGFBI-associated Corneal Dystrophies

Cited by 62 publications

References 108 publications

Clusterin in the eye: An old dog with new tricks at the ocular surface

Clusterin in the eye: An old dog with new tricks at the ocular surface

The Genetics and Pathophysiology of IC3D Category 1 Corneal Dystrophies

Transforming growth factor β induced mutation-associated phenotype in a Chinese family exhibiting lattice corneal dystrophy

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