Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022568 (keratitis)
 5,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant keratitis (ADK) is an eye disorder chiefly characterized by corneal opacification and vascularization and by foveal hypoplasia. Aniridia (shown recently to result from mutations in the PAX6 gene) has overlapping clinical findings and a similar pattern of inheritance with ADK. On the basis of these similarities, we used a candidate-gene approach to investigate whether mutations in the PAX6 gene also result in ADK. Significant linkage was found between two polymorphic loci in the PAX6 region and ADK in a family with 15 affected members in four generations (peak LOD score = 4.45; theta = .00 with D11S914), consistent with PAX6 mutations being responsible for ADK. SSCP analysis and direct sequencing revealed a mutation in the PAX6 exon 11 splice-acceptor site. The predicted consequent incorrect splicing results in truncation of the PAX6 proline-serine-threonine activation domain. The SeyNeu mouse results from a mutation in the Pax-6 exon 10 splice-donor site that produces a PAX6 protein truncated from the same point as occurs in our family with ADK. Therefore, the SeyNeu mouse is an excellent animal model of ADK. The finding that mutations in PAX6 underlie ADK, along with a recent report that mutations in PAX6 also underlie Peters anomaly, implicates PAX6 broadly in human anterior segment malformations.
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PMID:Mutation of the PAX6 gene in patients with autosomal dominant keratitis. 766 81

Mutations in the human PAX6 gene produce various phenotypes, including aniridia, Peters' anomaly, autosomal dominant keratitis and familial foveal dysplasia. The various phenotypes may arise from different mutations in the same gene. To test this theory, we performed a functional analysis of two missense mutations in the paired domain: the R26G mutation, previously reported in a case of Peters' anomaly, and an unreported I87R mutation, which we identified in a patient with aniridia. While both the R26 and the I87 positions are conserved in the paired boxes of all known PAX genes, X-ray crystallography has shown that only R26 makes contact with DNA. We showed that the R26G mutant failed to bind a subset of paired domain binding sites but, surprisingly, bound other sites and successfully transactivated promoters containing those sites. In contrast, the I87R mutant had lost the ability to bind DNA at all tested sites and failed to transactivate promoters. Our data support the haploid-insufficiency hypothesis of aniridia, and the hypothesis that R26G is a hypomorphic allele.
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PMID:Functional analysis of paired box missense mutations in the PAX6 gene. 914 40

Mutations in PAX6 are responsible for human aniridia and have also been found in patients with Peter's anomaly, with congenital cataracts, with autosomal dominant keratitis, and with isolated foveal hypoplasia. No locus other than chromosome 11p13 has been implicated in aniridia, and PAX6 is clearly the major, if not only, gene responsible. Twenty-eight percent of identified PAX6 mutations are C-T changes at CpG dinucleotides, 20% are splicing errors, and more than 30% are deletion or insertion events. There is a noticeably elevated level of mutation in the paired domain compared with the rest of the gene. Increased mutation in the homeodomain is accounted for by the hypermutable CpG dinucleotide in codon 240. Very nearly all mutations appear to cause loss of function of the mutant allele, and more than 80% of exonic substitutions result in nonsense codons. In a gene with such extraordinarily high sequence conservation throughout evolution, there are presumed undiscovered missense mutations, these are hypothesized to exist in as-yet unidentified phenotypes.
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PMID:PAX6 mutations reviewed. 948 72

Mutations in the human PAX6 gene are an important cause of dominantly inherited congenital malformations of the eye, including aniridia, Peters' anomaly, keratitis, and isolated foveal hypoplasia. To satisfy the need for efficient detection of PAX6 mutations, we have developed a new set of oligonucleotides for genomic SSCP based on the recently completed genomic sequence of the entire human PAX6 gene. We also describe PAX6 mutations in eight aniridia patients, five of which are novel.
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PMID:A new set of primers for mutation analysis of the human PAX6 gene. 967 Dec 74

PAX6 is a transcription factor with two DNA-binding domains (paired box and homeobox) and a proline-serine-threonine (PST)-rich transactivation domain. PAX6 regulates eye development in animals ranging from jellyfish to Drosophila to humans. Heterozygous mutations in the human PAX6 gene result in various phenotypes, including aniridia, Peter's anomaly, autosomal dominant keratitis, and familial foveal dysplasia. It is believed that the mutated allele of PAX6 produces an inactive protein and aniridia is caused due to genetic haploinsufficiency. However, several truncation mutations have been found to occur in the C-terminal half of PAX6 in patients with Aniridia resulting in mutant proteins that retain the DNA-binding domains but have lost most of the transactivation domain. It is not clear whether such mutants really behave as loss-of-function mutants as predicted by haploinsufficiency. Contrary to this theory, our data showed that these mutants are dominant-negative in transient transfection assays when they are coexpressed with wild-type PAX6. We found that the dominant-negative effects result from the enhanced DNA binding ability of these mutants. Kinetic studies of binding and dissociation revealed that various truncation mutants have 3-5-fold higher affinity to various DNA-binding sites when compared with the wild-type PAX6. These results provide a new insight into the role of mutant PAX6 in causing aniridia.
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PMID:Truncation mutations in the transactivation region of PAX6 result in dominant-negative mutants. 970 83

PAX6 is essential for ocular morphogenesis. Mutations in the PAX6 gene produce various phenotypes, including aniridia, Peters' anomaly, foveal hypoplasia, autosomal dominant keratitis and congenital cataracts. PAX6 functions as a transcription factor and has two DNA binding domains (a paired domain and a homeodomain) which are joined by a linker, and a transactivation domain enriched in proline, serine and threonine (PST) at the C-terminus. The mechanism of PAX6 function is not clearly understood, and few target genes in vertebrates have been identified. We examined disease-causing missense mutations in the PST domain to understand how they affect the function of PAX6. Upon examining the DNA samples of aniridia patients, we identified three missense mutations in the PST domain: P375Q (a novel mutation) and the previously reported Q422R and X423L mutations. On the basis of functional analysis, the P375Q mutant appears to have a normal transactivation activity but lower DNA binding through the paired domain than the wild-type. The Q422R mutation resulted in the loss of DNA binding ability of the PAX6 homeodomain. Substitution analyses of the C-terminal amino acid (codon 422) indicated that an amino acid at codon 422 is required for DNA binding of the homeodomain of intact PAX6 and that the polarity and charge of the side-chain of the terminal amino acid influence this binding.
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PMID:Missense mutation at the C-terminus of PAX6 negatively modulates homeodomain function. 1130 64

The PAX6 mutation present in an individual with aniridia was determined and phenotypic features of immediate relatives carrying the same mutation investigated. Mutation analysis revealed a novel single base deletion 1410delC in the PAX6 gene in ten affected individuals. Clinical features ranged from total aniridia to very mild anterior segment findings. Other findings included partial aniridia, iris stromal hypoplasia, keratitis, cataract, glaucoma, optic disc anomalies and foveal hypoplasia. It appears that independent modifying factors may underlie the variability of the different phenotypic features of the PAX6 mutation.
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PMID:Broad phenotypic variability in a single pedigree with a novel 1410delC mutation in the PST domain of the PAX6 gene. 1232 30

Autosomal dominant microphthalmia with late-onset keratitis and iris coloboma/aniridia has not been reported before. Here we report a Chinese family with these phenotypes and a novel PAX6 mutation. Microphthalmia, late-onset keratitis, iris coloboma, and nystagmus were present in the proband. His son had microphthalmia, aniridia, foveal hypoplasia, and nystagmus. A novel c.649C>T (p.Arg217X) mutation in PAX6 was detected in the proband and his affected son. This study expands the phenotypic spectrum of PAX6 mutation and enriched our knowledge of the genetic cause for microphthalmia and late-onset keratitis.
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PMID:Microphthalmia, late onset keratitis, and iris coloboma/aniridia in a family with a novel PAX6 mutation. 2217 86

Aniridia classically presents with a bilateral congenital absence or malformation of the irides, foveal hypoplasia, and nystagmus, and patients tend to develop visually significant pre-senile cataracts and keratopathy. Additionally, they are at high risk for developing glaucoma. Classic aniridia can be genetically defined as the presence of a PAX6 gene deletion or loss-of-function mutation that results in haploinsufficiency. Variants of aniridia, which include a condition previously referred to as autosomal dominant keratitis, are likely due to PAX6 mutations that lead to partial loss of PAX6 function. Aniridia-associated keratopathy (AAK) is a progressive and potentially debilitating problem affecting aniridic patients. The current treatments for AAK are to replace the limbal stem cells through keratolimbal allograft (KLAL) with or without subsequent keratoplasty for visual rehabilitation, or to implant a Boston type 1 keratoprosthesis. Future therapies for AAK may be aimed at the genetic modification of corneal limbal stem cells.
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PMID:A review of the clinical and genetic aspects of aniridia. 2413 39