Mutations in KERA, encoding keratocan, cause cornea plana (original) (raw)
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A novel KERA mutation associated with autosomal recessive cornea plana
Ophthalmic Genetics, 2004
To report a novel KERA mutation associated with autosomal recessive cornea plana in members of a nuclear family and to describe their ophthalmic phenotypes. Ophthalmic examination, biometry, and direct sequencing of KERA. Five of the 6 siblings were affected and had small flat corneas, variable anterior chamber depths, and short axial lengths. The remaining brother and the 2 parents had normal ophthalmic examinations. Genetic testing revealed a novel homozygous nonsense mutation in exon 3 [937C>T] in the clinically affected individuals. The clinically unaffected parents were confirmed as carriers. The clinically unaffected sibling had no KERA mutation. This mutation leads to replacement of an arginine by a stop codon at position 313 of keratocan protein. This novel point mutation in KERA is the fourth thus far described. The ocular phenotype is characteristic of autosomal recessive cornea plana.
BMC Medical Genetics, 2015
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Clinical and Molecular Characterization of a Family With Autosomal Recessive Cornea Plana
Archives of Ophthalmology, 2005
Background: Autosomal recessive cornea plana is characterized by a flattened corneal surface associated with hyperopia and various anterior segment abnormalities. Mutations have been detected in the keratocan gene (KERA), a member of the small leucine-rich proteoglycan family. Objective: To clinically and molecularly characterize a consanguineous family of Hispanic origin in which 3 individuals are affected with cornea plana. Methods: Clinical ophthalmic examination, including corneal topography and axial eye length measurement, was performed on 7 family members. Molecular analysis of KERA was performed on DNA from each family member who had been examined. Results: All 3 affected individuals showed extreme flattening of the cornea (Ͻ36 diopters [D]), normal axial eye lengths, and hyperopia greater than 6.25 D (spherical equivalent). Anterior segment abnormalities included scleralization of the cornea and central iris strands to the corneal endothelium. Affected individuals were homozygous for a novel mutation in KERA. The sequence change was found in exon 2, which results in an asparagine to aspartic acid change at codon 131. This amino acid change occurs within a highly conserved leucinerich repeat of keratocan. Conclusions: The cause of disease in this family is likely to be a mutation in exon 2 of KERA. Other mutations in KERA known to cause cornea plana also fall within the region encoding the leucine-rich repeat motifs and are predicted to affect the tertiary structure of the protein. Clinical Relevance: This is the first report of the identification of a mutation within KERA in a family of Hispanic origin with autosomal recessive cornea plana. Although the vast majority of cases of cornea plana are in individuals of Finnish descent, this report demonstrates the occurrence of the disease in other populations.
Molecular vision, 2008
Juvenile epithelial corneal dystrophy of Meesmann (MCD, OMIM 122100) is a dominantly inherited disorder characterized by fragility of the anterior corneal epithelium and intraepithelial microcyst formation. Although the disease is generally mild and affected individuals are often asymptomatic, some suffer from recurrent erosions leading to lacrimation, photophobia, and deterioration in visual acuity. MCD is caused by mutations in keratin 3 (KRT3) or keratin 12 (KRT12) genes, which encode cornea-specific cytoskeletal proteins. Seventeen mutations in KRT12 and two in KRT3 have been described so far. The purpose of this study was to investigate the genetic background of MCD in a Polish family. We report on a three-generation family with MCD. Epithelial lesions characteristic for MCD were visualized with slit-lamp examination and confirmed by in vivo confocal microscopy. Using genomic DNA as a template, all coding regions of KRT3 and KRT12 were amplified and sequenced. Presence of the m...
Keratocan-deficient Mice Display Alterations in Corneal Structure
Journal of Biological Chemistry, 2003
Keratocan (Kera) is a cornea-specific keratan sulfate proteoglycan (KSPG) in the adult vertebrate eye. It belongs to the small leucine-rich proteoglycan (SLRP) gene family and is one of the major components of extracellular KSPG in the vertebrate corneal stroma. The Kera gene is expressed in ocular surface tissues including cornea and eyelids during morphogenesis. Corneal KSPGs play a pivotal role in matrix assembly, which is accountable for corneal transparency. In humans, mutations of the KERA gene are associated with cornea plana (CNA2) that manifests decreases in vision acuity due to the flattened forward convex curvature of cornea. To investigate the biological role of the Kera gene and to establish an animal model for corneal plana, we generated Kera knockout mice via gene targeting. Northern and Western blotting and immunohistochemical analysis showed that no Kera mRNA or keratocan protein was detected in the Kera ؊/؊ cornea. The expression levels of other SLRP members including lumican, decorin, and fibromodulin were not altered in the Kera ؊/؊ cornea as compared with that of the wild-type littermates. Mice lacking keratocan have normal corneal transparency at the age of 12 months. However, they have a thinner corneal stroma and a narrower cornea-iris angle of the anterior segment in comparison to the wild-type littermates. As demonstrated by transmission electron microscopy, Kera ؊/؊ mice have larger stromal fibril diameters and less organized packing of collagen fibrils in stroma than those of wild type. Taken together, our results showed that ablation of the Kera gene resulted in subtle structural alterations of collagenous matrix and did not perturb the expression of other SLRPs in cornea. Keratocan thus plays a unique role in maintaining the appropriate corneal shape to ensure normal vision. The abbreviations used are: SLRP, small leucine-rich proteoglycan; KO, knockout; KS, keratan sulfate; E, embryonic day.
Genetics in Keratoconus – What is New?
The Open Ophthalmology Journal, 2017
Background: Keratoconus is characterized as a bilateral, progressive, non-inflammatory thinning of the cornea resulting in blurred vision due to irregular astigmatism. Keratoconus has a multifactorial etiology, with multiple genetic and environmental components contributing to the disease pathophysiology. Several genomic loci and genes have been identified that highlight the complex molecular etiology of this disease. Conclusion: The review focuses on current knowledge of these genetic risk factors associated with keratoconus.
Genetics of Keratoconus: Where Do We Stand?
Journal of Ophthalmology, 2014
Keratoconus is a progressive thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced vision. Keratoconus has a complex multifactorial etiology, with environmental, behavioral, and multiple genetic components contributing to the disease pathophysiology. Using genome-wide and candidate gene approaches several genomic loci and genes have been identified that highlight the complex molecular etiology of this disease. The review focuses on current knowledge of these genetic risk factors associated with keratoconus.
Genomic strategies to understand causes of keratoconus
Molecular Genetics and Genomics
com thinning, which results in the conical shape of the cornea. These structural changes in the corneal layers induce optical aberrations, leading to a loss of visual acuity due to distorted blurred vision, which is caused by irregular astigmatism, and high myopia (Rabinowitz 1998). Although KTCN is sometimes referred to as a corneal dystrophy, it is not included in International Classification of Corneal Dystrophies (IC3D) (Weiss et al. 2008) and should be distinguished from this group of corneal diseases. However, co-occurrence of KTCN with many types of corneal dystrophies, including Avellino and Fuchs dystrophies (Igarashi et al. 2003; Salouti et al. 2010; Wilson et al. 2014), may indicate that common molecular mechanisms in the pathogenesis of these disorders are involved. Among the general population, the estimated frequency of KTCN is 1 in 2,000 individuals (Rabinowitz 1998), although up-to-date data are not available. The prevalence of KTCN may be different according to patient ethnic origin (Gokhale 2013). The reported prevalence of the disease may also vary depending upon the different diagnostic tests used in the particular studies. The early KTCN or forme fruste KTCN are not detectable at the slit lamp during the anterior segment examination, and in these cases, assessment of the corneal topographic pattern is required to obtain the accurate diagnosis (Saad and Gatinel 2010). The first symptoms of KTCN usually appear during the second decade or early in the third decade of life. The pathogenic features of KTCN may be observed in different layers of the cornea (Fig. 1) (Sherwin and Brookes 2004). These abnormalities include changes in morphology of epithelial cells (Sykakis et al. 2012), deposition of iron particles in the epithelial basement membrane, breaks in Bowman's layer (Rabinowitz 1998), and thinning of stroma correlating with loss of collagen lamellae, altered collagen fibril orientation, and decreased keratocytes density (Patey et al.
Molecular and Histopathological Changes Associated with Keratoconus
BioMed Research International, 2017
Keratoconus (KC) is a corneal thinning disorder that leads to loss of visual acuity through ectasia, opacity, and irregular astigmatism. It is one of the leading indicators for corneal transplantation in the Western countries. KC usually starts at puberty and progresses until the third or fourth decade; however its progression differs among patients. In the keratoconic cornea, all layers except the endothelium have been shown to have histopathological structural changes. Despite numerous studies in the last several decades, the mechanisms of KC development and progression remain unclear. Both genetic and environmental factors may contribute to the pathogenesis of KC. Many previous articles have reviewed the genetic aspects of KC, but in this review we summarize the histopathological features of different layers of cornea and discuss the differentially expressed proteins in the KC-affected cornea. This summary will help emphasize the major molecular defects in KC and identify additional research areas related to KC, potentially opening up possibilities for novel methods of KC prevention and therapeutic intervention.