PAX6 missense mutations associated in patients with opticnerve malformation

[摘要] Purpose: PAX6 missense mutations are likely to cause a spectrumof ocular, neurological, and systemic developmental defects and havebeen reported in various ethnic groups. The purpose of this study was toinvestigate the clinical features of optic nerve malformation caused byPAX6 mutations in Indian patients.Methods: Total genomic DNA was isolated from peripheral blood of 27sporadic probands affected with congenital optic nerve malformation,unaffected family members, and 50 unrelated age-matched controls.Informed consent was obtained from all study subjects. Polymerase chainreaction was carried out to explore PAX6 defective alleles usingsingle-strand conformation analysis (PCR-SSCA) followed by automatedbidirectional sequencing.Results: We identified two novel PAX6 missense mutations in twounrelated sporadic probands. The mutation analysis revealed variation atposition c.469G>C, codon 36 in proband ONH 4-1 with optic nervehypoplasia. The other de novo mutation was observed at c.514G>C,codon 51 in proband ODC 5-1 with optic disc coloboma. Both G>C basesubstitutions cause a relatively conservative amino acid change,altering glycine to alanine residues within the paired DNA-bindingdomain.Conclusions: In this study, we have been able to identify twosequence variations in the PAX6 gene. These missense mutations mayuniquely alter the structure and expression of PAX6 protein, resultingin distinct clinical phenotypes. Mutation analysis of 27 probands forPAX6 has resulted in only two significant variants. This findingdemonstrated that the frequency of PAX6 mutations associated withoptic nerve malformation is low, requiring the elucidation of othercandidate genes in other patients.

[学科分类] 生物化学/生物物理