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Mutation in the PAX6 gene in twenty patients with aniridia
1Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
This is a report on the nature of the mutations in the PAX6 gene in twenty patients with aniridia. Five of the twenty patients had sporadic aniridia with deletions in chromosome 11p13. Three of the five had WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, mental retardation), and the other two had deletions whose breakpoints occurred between the PAX6 and the WT1 genes. Allelic losses at PAX6 were of paternal origin. The remaining fifteen patients with aniridia had intragenic mutations in the PAX6 gene, with mutations found from exon 5 to exon 12. Twelve cases of dysfunctional PAX6 were due to premature termination of the protein by nonsense mutations (five cases), splicing defect (one case), deletion (two cases), deletion-insertions (two cases), and tandem repeat insertions (two cases). One patient (P2) had a PAX6 protein with de novo in-frame deletion of alanine, arginine, and proline at codon positions 37, 38, and 39. These codons are in the paired box region, and codon 38 is in contact with the phosphate group of the sugar-phosphate backbone of the target DNA. Another patient (P8) had a single nucleotide transition at c.1182 (nucleotide number, Genbank accession #M93650, used as in Glaser et al. [1992]), which generated both a missense mutation (Q255H) and a splicing defect. A missense mutation was found at G387E in a third patient (P10). All observed mutations support the notion that haploinsufficiency in PAX6 results in aniridia and associated eye anomalies.
Insights
Mutations in the PAX6 gene cause aniridia (a severe eye condition). Both large deletions and smaller intragenic mutations in PAX6 lead to haploinsufficiency, resulting in aniridia and related eye abnormalities.
Area of Science:
- Genetics
- Ophthalmology
- Developmental Biology
Background:
- Aniridia is a congenital eye disorder characterized by the absence of the iris.
- The PAX6 gene plays a crucial role in eye development.
- Mutations in PAX6 are a known cause of aniridia.
Purpose of the Study:
- To investigate the nature and spectrum of mutations in the PAX6 gene in patients with aniridia.
- To correlate specific PAX6 mutations with clinical phenotypes, including WAGR syndrome.
- To understand the mechanism of PAX6 haploinsufficiency in aniridia pathogenesis.
Main Methods:
- Genetic analysis of the PAX6 gene in twenty aniridia patients.
- Detection of deletions in chromosome 11p13 using molecular techniques.
- Identification of intragenic PAX6 mutations, including nonsense, splicing, deletion, deletion-insertion, and tandem repeat mutations.
- Analysis of de novo and missense mutations within the PAX6 gene.
Main Results:
- Five patients had sporadic aniridia with 11p13 deletions, including three with WAGR syndrome.
- Fifteen patients exhibited intragenic PAX6 mutations (exons 5-12), often leading to premature protein termination.
- Specific mutations identified include nonsense, splicing defects, deletions, deletion-insertions, tandem repeat insertions, de novo in-frame deletions, and missense mutations.
- Paternal origin of allelic losses at PAX6 was observed in deletion cases.
Conclusions:
- PAX6 haploinsufficiency is the underlying mechanism for aniridia and associated eye anomalies.
- A wide spectrum of mutations in the PAX6 gene, from large deletions to intragenic alterations, can cause aniridia.
- Understanding these mutations provides insights into the genetic basis of eye development and congenital disorders.