Dataset Information

Sequence alterations in RX in patients with microphthalmia, anophthalmia, and coloboma.

ABSTRACT: Microphthalmia, anophthalmia, and coloboma are ocular malformations with a significant genetic component. Rx is a homeobox gene expressed early in the developing retina and is important in retinal cell fate specification as well as stem cell proliferation. We screened a group of 24 patients with microphthalmia, coloboma, and/or anophthalmia for RX mutations.We used standard PCR and automated sequencing techniques to amplify and sequence each of the three RX exons. Patients' charts were reviewed for clinical information. The pathologic impact of the identified sequence variant was analyzed by computational methods using PolyPhen and PMut algorithms.In addition to the polymorphisms we identified a single patient with coloboma having a heterozygous nucleotide change (g.197G>C) in the first exon that results in a missense mutation of arginine to threonine at amino acid position 66 (R66T). In silico analysis predicted R66T to be a deleterious mutation.Sequence variations in RX are uncommon in patients with congenital ocular malformations, but may play a role in disease pathogenesis. We observed a missense mutation in RX in a patient with a small, typical chorioretinal coloboma, and postulate that the mutation is responsible for the patient's phenotype.

SUBMITTER: London NJ

PROVIDER: S-EPMC2628315 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Sequence alterations in RX in patients with microphthalmia, anophthalmia, and coloboma.

London Nikolas J S NJ Kessler Patricia P Williams Bryan B Pauer Gayle J GJ Hagstrom Stephanie A SA Traboulsi Elias I EI

Molecular vision 20090121

<h4>Purpose</h4>Microphthalmia, anophthalmia, and coloboma are ocular malformations with a significant genetic component. Rx is a homeobox gene expressed early in the developing retina and is important in retinal cell fate specification as well as stem cell proliferation. We screened a group of 24 patients with microphthalmia, coloboma, and/or anophthalmia for RX mutations.<h4>Methods</h4>We used standard PCR and automated sequencing techniques to amplify and sequence each of the three RX exons. ...[more]

PMID: 19158959

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Project description:PURPOSE:Anophthalmia and microphthalmia (A/M) are rare congenital ocular malformations presenting with the absence of eye components or small eyes with or without structural abnormalities. A/M can be isolated or syndromic. The stimulated by retinoic acid gene 6 (STRA6) and Sloan-Kettering viral oncogene homolog (SKI) genes are involved in vitamin A metabolism, and are implicated with A/M developmental abnormalities in human and animal studies. Vitamin A metabolism is vital to normal eye development and growth. This study explores the association of these genes in a cohort of subjects with A/M. METHODS:STRA6 and SKI were screened for sequence variants by direct sequencing of genomic DNA samples from 18 affected subjects with A/M. The DNA samples of 4 external, unrelated controls were initially screened. Eighty-nine additional unrelated controls were screened to confirm that any sequence variants found in the affected subject DNA samples were related to the phenotype. Coding regions, intron-exon boundaries, and untranslated regions were sequenced by standard techniques. Derived DNA sequences were compared to known reference sequences from public genomic databases. RESULTS:For STRA6, a novel coding non-synonymous sequence variant was found in one subject, resulting in an amino acid change from glycine to glutamic acid in residue 217. One novel nonsense sequence variant found in the same subject changed the STRA6 amino acid residue 592 from cytosine to thymine resulting in a premature stop codon. For SKI, a known coding non-synonymous sequence variant (rs28384811) was found in 3 subject DNA samples and 11/89 control DNA samples. Four novel coding-synonymous sequence variants were observed in SKI. CONCLUSIONS:The STRA6 sequence variants reported in this study could play a role in the pathogenesis of A/M by structural changes to the STRA6 protein. We can attribute 4% A/M incidence in this cohort to these sequence variants. Although no SKI sequence variants were found in this cohort, SKI should not be ruled out as a candidate gene for A/M due to the small cohort size.

Project description:Anophthalmia and microphthalmia describe, respectively, the absence of an eye and the presence of a small eye within the orbit. The combined birth prevalence of these conditions is up to 30 per 100,000 population, with microphthalmia reported in up to 11% of blind children. High-resolution cranial imaging, post-mortem examination and genetic studies suggest that these conditions represent a phenotypic continuum. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome, as in one-third of cases. Anophthalmia/microphthalmia have complex aetiology with chromosomal, monogenic and environmental causes identified. Chromosomal duplications, deletions and translocations are implicated. Of monogenic causes only SOX2 has been identified as a major causative gene. Other linked genes include PAX6, OTX2, CHX10 and RAX. SOX2 and PAX6 mutations may act through causing lens induction failure. FOXE3 mutations, associated with lens agenesis, have been observed in a few microphthalmic patients. OTX2, CHX10 and RAX have retinal expression and may result in anophthalmia/microphthalmia through failure of retinal differentiation. Environmental factors also play a contributory role. The strongest evidence appears to be with gestational-acquired infections, but may also include maternal vitamin A deficiency, exposure to X-rays, solvent misuse and thalidomide exposure. Diagnosis can be made pre- and post-natally using a combination of clinical features, imaging (ultrasonography and CT/MR scanning) and genetic analysis. Genetic counselling can be challenging due to the extensive range of genes responsible and wide variation in phenotypic expression. Appropriate counselling is indicated if the mode of inheritance can be identified. Differential diagnoses include cryptophthalmos, cyclopia and synophthalmia, and congenital cystic eye. Patients are often managed within multi-disciplinary teams consisting of ophthalmologists, paediatricians and/or clinical geneticists, especially for syndromic cases. Treatment is directed towards maximising existing vision and improving cosmesis through simultaneous stimulation of both soft tissue and bony orbital growth. Mild to moderate microphthalmia is managed conservatively with conformers. Severe microphthalmia and anophthalmia rely upon additional remodelling strategies of endo-orbital volume replacement (with implants, expanders and dermis-fat grafts) and soft tissue reconstruction. The potential for visual development in microphthalmic patients is dependent upon retinal development and other ocular characteristics.

Dataset Information

Sequence alterations in RX in patients with microphthalmia, anophthalmia, and coloboma.

Publications

Sequence alterations in RX in patients with microphthalmia, anophthalmia, and coloboma.

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