Autosomal Recessive Cornea Plana Research Articles

Multimodal imaging of autosomal recessive cornea plana associated with hard mature and polar cataract

Multimodal imaging of autosomal recessive cornea plana associated with hard mature and polar cataract

A Novel KERA Mutation in a Case of Autosomal Recessive Cornea Plana With Primary Angle-Closure Glaucoma.

Keratocan is a cornea-specific keratan sulfate proteoglycan found predominantly in the adult vertebrate eye. In human beings, mutations in keratocan (KERA) are associated with autosomal recessive cornea plana (CNA2), which is characterized by a flattened forward convex curvature of the cornea. Here, we report a novel mutation in a case of autosomal recessive bilateral cornea plana presenting with primary angle-closure glaucoma in a 41-year-old woman from Eastern India. The KERA gene of the patient and her sons was directly sequenced. Mutational analysis of the KERA revealed 2 novel mutations. The first mutation was a 3 base-pair deletion (c.371_373delTCT), leading to the loss of a highly conserved amino acid (p.Phe125del). The second mutation was a base substitution resulting in a silent mutation (c.69G>A). One of her 2 sons carried the homozygous substitution (c.69G>A), whereas the other son was heterozygous (c.69G>R). The mutation that we report here leads to the deletion of a conserved amino acid (p.Phe125del) from the third LRR motif of the keratocan protein, which might lead to an abnormal tertiary structure of the protein, thereby leading to the disease.

Autosomal Dominant Cornea Plana is not Associated with Pathogenic Mutations in DCN, DSPG3, FOXC1, KERA, LUM, or PITX2

Purpose: To determine the genetic basis of autosomal dominant cornea plana (CNA1) through the performance of a genome-wide linkage analysis and screening of the decorin (DCN), dermatan sulfate proteoglycan 3 (DSPG3), forkhead box C1 (FOXC1), keratocan (KERA), lumican (LUM,) and paired-like homeodomain transcription factor 2 (PITX2) genes in members of an affected multigenerational family. Methods: Cycloplegic refraction, slit lamp biomicroscopy, corneal pachymetry, and corneal topography were performed to determine each patient's affected status. DNA was obtained from affected and unaffected subjects for the performance of a genome-wide linkage analysis as well as PCR amplification and sequencing of DCN, DSPG3, FOXC1, KERA, LUM, and PITX2. Results: Five affected and three unaffected individuals were examined and provided a peripheral blood sample for DNA isolation. All affected individuals demonstrated an average corneal dioptric power less than 39 D, as well as one or more of the following anomalies: high hyperopia, strabismus, microcornea, posterior embryotoxon, iridocorneal adhesions, iris atrophy, and pupillary irregularities. A genome-wide linkage analysis did not indicate or exclude linkage to the region on chromosome 12 to which CNA1 has been previously mapped, and did not provide a single or multipoint LOD score greater than 2.0 for any of the 400 microsatellite markers. Screening of DCN, DSPG3, FOXC1, KERA, LUM, and PITX2 revealed 12 previously described single nucleotide polymorphisms, 2 previously described duplications, and 1 previously described insertion. None of the mutations previously associated with autosomal recessive cornea plana (CNA2) were identified. Seven novel sequence variants were described, including 5 single nucleotide substitutions, 1 insertion and 1 deletion. None of the identified sequence variants demonstrated complete segregation with the affected phenotype in the pedigree. Conclusion: Although missense and nonsense mutations in KERA are associated with CNA2, we did not identify any of the previously described mutations or novel mutations that segregated with the disease phenotype in a family with CNA1. In addition, no pathogenic sequence variations were found in DCN, DSPG3, LUM, PITX2 and FOXC1, which have also been implicated in corneal and anterior segment dysgenesis.

Corneal Ectasia and Hydrops in a Patient with Autosomal Recessive Cornea Plana

Purpose: To report the development of corneal ectasia and hydrops in a patient with autosomal recessive cornea plana. Methods: Retrospective observational case report. Results: A 16-year-old male with a prior diagnosis of autosomal recessive cornea plana who complained of unilateral visual loss of one month's duration was found to have corneal edema consistent with resolving hydrops in the affected eye. The edema resolved over time, and keratometry revealed high astigmatism in both eyes despite documentation of no significant corneal astigmatism 11 years before. Slit-lamp examination confirmed corneal thinning in both eyes corresponding to the meridian of the astigmatism. The prior diagnosis of cornea plana was confirmed by molecular genetic testing. Conclusions: Although not a characteristic finding of cornea plana, corneal ectasia can rarely occur and be associated with corneal hydrops.

Clinical and Molecular Characterization of a Family With Autosomal Recessive Cornea Plana

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. To clinically and molecularly characterize a consanguineous family of Hispanic origin in which 3 individuals are affected with cornea plana. 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. All 3 affected individuals showed extreme flattening of the cornea (< 36 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 leucine-rich repeat of keratocan. 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. 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.

A novel KERAmutation associated with autosomal recessive cornea plana

Purpose:To report a novel KERAmutation associated with autosomal recessive cornea plana in members of a nuclear family and to describe their ophthalmic phenotypes. Methods:Ophthalmic examination, biometry, and direct sequencing of KERA. Results: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 KERAmutation. This mutation leads to replacement of an arginine by a stop codon at position 313 of keratocan protein. Conclusions:This novel point mutation in KERAis the fourth thus far described. The ocular phenotype is characteristic of autosomal recessive cornea plana.

Autosomal recessive cornea plana. A clinical and genetic study of 78 cases in Finland.

To review the literature of autosomal recessive cornea plana (RCP) and to perform a clinical and genetic study on this disorder in Finland. The 78 Finnish RCP patients represent the majority of RCP cases worldwide; outside Finland only 35 cases have been reported. Families with RCP, particularly in northern Finland, have been followed up by the senior author since the 1950s and extensive genealogical studies have been made. The most typical symptoms are greatly reduced corneal refraction, 25-35 dioptres, causing strong hyperopia, slight microcornea, an extended limbus zone, a central, deep corneal opacity and a marked arcus senilis, seen even before the age of 20. We present a pedigree comprising 33 affected persons with cornea plana. We have mapped the two genes for the dominantly and the recessively inherited type of cornea plana to the same region on the long arm of chromosome 12, (12q21). In northern Finland RCP has a higher frequency than elsewhere, probably as a result of a strong founder effect in the population that arrived in these regions approx. 400 years ago. The strong accumulation of this rare disease in these isolated areas and the strong genealogical connections between different families with RCP, suggest that probably all the Finnish RCP cases are caused by the same mutation.

Linkage Disequilibrium Mapping of the Cornea Plana Congenita Gene CNA2

We recently assigned a gene for autosomal recessive cornea plana congenita (CNA2; MIM No. 217300) by linkage analysis to the approximately 3-cM interval between markers D12S82 and D12S327. Here, we extended these studies by exploiting the haplotype and linkage disequilibrium information that can be derived from the genetically isolated Finnish population and its subpopulations. By testing 32 independent families with 10 polymorphic markers in the CNA2 interval, strong allelic association between CNA2 and a set of markers with a peak at marker D12S351 was detected. Based on linkage disequilibrium analysis, the critical region for CNA2 could be narrowed to only 0.04-0.3 cM from marker D12S351, thus defining a critical interval 0.08-0.60 cM in length. These results provide a basis for highly focused positional cloning of CNA2.

Cornea plana congenita gene assigned to the long arm of chromosome 12 by linkage analysis

We report the mapping of the locus for autosomal recessive cornea plana congenita (CNA2; MIM 217300) by linkage analysis to the approximately 10-cM interval between markers D12S82 and D12S327. The recessively inherited disorder studied here is more severe than dominant forms. Its main manifestations are reduced curvature and hazy limbus of the cornea, opacities in the corneal stroma, and marked corneal arcus at early age. Our results provide a starting point for the positional cloning of CNA2 and the elucidation of the pathogenesis of the disease.