Linkage of Late-Onset Fuchs Corneal Dystrophy to a Novel Locus at 13pTel-13q12.13

Sundin, Olof; Jun, Albert S.; Broman, Karl W.; Liu, Sammy H.; Sheehan, Siobhan E.; Vito, Elizabeth C.L.; Stark, Walter J.; Gottsch, John D.

doi:10.1167/iovs.05-0578

Cited by 103 publications

(75 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…19 A total of 13 affected and 3 unaffected individuals across three generations were recruited for genotyping, and linkage using 399 STR markers from the MD10 genotyping panel revealed significant two-point logarithm of odds scores of 3.91 at D13S1236 and 3.80 at D13S1304, assuming fully penetrant dominant inheritance. Notably, two children in this family whose parents were both affected demonstrated clinical signs of late-onset FCD at a young age.…”

Section: Genetic Linkage Analysismentioning

confidence: 99%

Fuchs Corneal Dystrophy

Eghrari

Riazuddin

Gottsch

2015

Progress in Molecular Biology and Translational Science

Self Cite

View full text Add to dashboard Cite

Section: Genetic Linkage Analysismentioning

confidence: 99%

Fuchs Corneal Dystrophy

Eghrari

Riazuddin

Gottsch

2015

Progress in Molecular Biology and Translational Science

Self Cite

View full text Add to dashboard Cite

“…The endothelial layer also allows aqueous to 'leak' into the stroma, delivering metabolites to the stromal cells and increasing the need for endothelial pump activity. Damage to the transport capability of the endothelium, usually caused by loss of endothelial cells from damage [30], hereditary disease [31,32], or aging [33], leads to swelling of the stroma and loss of transparency.…”

Section: Nutrient and Oxygen Supply To The Cornea And Lensmentioning

confidence: 99%

Maintaining transparency: A review of the developmental physiology and pathophysiology of two avascular tissues

Beebe

2008

Seminars in Cell & Developmental Biology

111

View full text Add to dashboard Cite

The lens and cornea are transparent and usually avascular. Controlling nutrient supply while maintaining transparency is a physiological challenge for both tissues. During sleep and with contact lens wear the endothelial layer of the cornea may become hypoxic, compromising its ability to maintain corneal transparency. The mechanism responsible for establishing the avascular nature of the corneal stroma is unknown. In several pathological conditions, the stroma can be invaded by abnormal, leaky vessels, leading to opacification. Several molecules that are likely to help maintain the avascular nature of the corneal stroma have been identified, although their relative contributions remain to be demonstrated. The mammalian lens is surrounded by capillaries early in life. After the fetal vasculature regresses, the lens resides in a hypoxic environment. Hypoxia is likely to be required to maintain lens transparency. The vitreous body may help to maintain the low oxygen level around the lens. The hypothesis is presented that many aspects of the aging of the lens, including increased hardening, loss of accommodation (presbyopia), and opacification of the lens nucleus, are caused by exposure to oxygen. Testing this hypothesis may lead to prevention for nuclear cataract and insight into the mechanisms of lens aging. Although they are both transparent, corneal pathology is associated with an insufficient supply of oxygen, while lens pathology may involve excessive exposure to oxygen. Keywords hypoxia; neovascularization; cataract; avascular; oxygen Developmental PhysiologyThe lens and cornea have physiological similarities and structural differences. In spite of their different anatomical features, for both tissues to maintain transparency, their cells must obtain needed metabolites and be protected from harmful influences from the environment. The manner in which the lens and cornea manage these physiological challenges and the impact of these solutions on their function and pathology are the topic of this review.A dominant feature of the physiology of the lens and cornea of most mammals is their avascular nature in adult life. The cornea is avascular at all stages of its development. In mammals, the fetal lens is invested with a network of capillaries that regresses late in fetal or early postnatal life.

show abstract

“…Three FECD susceptibility genomic loci 1p34.3-32, 13q12.11-q12.13, and 18q21.2-q21.32 have been previously identified through linkage studies of multigenerational families with autosomal-dominant FECD. 8,10,11 On the basis of studies reporting significant linkage of FECD, several pathogenic mutations in the collagen type VIII a2 gene (COL8A2), located on 1p34.3-p32, have been detected in affected individuals with FECD, and a strong association between FECD patients and genetic variants of COL8A2 has been validated by multiple studies. [6][7][8]12 In particular, two missense mutations, L450W and Q455K, showed perfect concordance in an FECD family having early onset and are positioned within the triple-helical domain of a2 collagen type VIII, which leads to the structural alteration of Descemet's membrane.…”

Section: Introductionmentioning

confidence: 99%

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

Mok

Kim

Joo

2008

Eye

View full text Add to dashboard Cite

Purpose To investigate the possibility of collagen type VIII a2 (COL8A2) as a potential susceptibility gene for Korean patients with Fuchs' corneal dystrophy (FECD), we performed mutation screening of the COL8A2 gene. Methods A total of 25 FECD patients were screened, including 15 patients from six pedigrees with early onset FECD and an additional 10 unrelated patients, all of Korean ancestry. Seventy-three control individuals without corneal disease were selected from the general population. PCRFSSCP and direct sequencing were used to screen genetic variations in COL8A2. The pathogenic impact of these sequence variants was evaluated through the SIFT and PolyPhen algorithms.Results We have identified a novel heterozygous mutation, Q455V, in exon 2 of COL8A2. All patients of Korean pedigrees with FECD had the Q455V mutation, and two out of nine unrelated cases also had this mutation. But it was not present in unaffected individuals from these pedigrees or from control groups. Two heterozygous missense mutations, R155Q and T502M, were also observed, but, they showed no significant difference between FECD patients and controls. The allele frequencies of A35A and G495G, which were synonymous substitutions, were significantly associated with FECD. Both Q455V and T502M were predicted as deleterious mutations by computational methods using PolyPhen and SIFT. Conclusions Our data constitute the first report of a heterozygous Q455V mutation of the COL8A2 gene in Korean patients with FECD. Q455V may be the causative defect in the development and progression of Korean FECD patients.

show abstract

Linkage of Late-Onset Fuchs Corneal Dystrophy to a Novel Locus at 13pTel-13q12.13

Abstract: FCD1 is the first genetic locus to be identified for late-onset FCD, a common disease of the aging cornea. The exceptional early onset of the disease observed in two children is unusual and might be the result of digenic interaction between FCD1 and an independent late-onset FCD mutation.

Cited by 103 publications

References 20 publications

Fuchs Corneal Dystrophy

Fuchs Corneal Dystrophy

Maintaining transparency: A review of the developmental physiology and pathophysiology of two avascular tissues

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

Contact Info

Product

Resources

About