title: PAX6 missense mutations associated in patients with optic nerve malformation.
abstract: OBJECTIVE
  PAX6 missense mutations are likely to cause a spectrum of ocular, neurological, and systemic developmental defects and have been reported in various ethnic groups. The purpose of this study was to investigate the clinical features of optic nerve malformation caused by PAX6 mutations in Indian patients.
  
  
  METHODS
  Total genomic DNA was isolated from peripheral blood of 27 sporadic 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 chain reaction was carried out to explore PAX6 defective alleles using single-strand conformation analysis (PCR-SSCA) followed by automated bidirectional sequencing.
  
  
  RESULTS
  We identified two novel PAX6 missense mutations in two unrelated sporadic probands. The mutation analysis revealed variation at position c.469G>C, codon 36 in proband ONH 4-1 with optic nerve hypoplasia. 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 base substitutions cause a relatively conservative amino acid change, altering glycine to alanine residues within the paired DNA-binding domain.
  
  
  CONCLUSIONS
  In this study, we have been able to identify two sequence variations in the PAX6 gene. These missense mutations may uniquely alter the structure and expression of PAX6 protein, resulting in distinct clinical phenotypes. Mutation analysis of 27 probands for PAX6 has resulted in only two significant variants. This finding demonstrated that the frequency of PAX6 mutations associated with optic nerve malformation is low, requiring the elucidation of other candidate genes in other patients.
authors.affiliation: Department of Genetics, Aravind Medical Research Foundation, Madurai, India.
authors.forename: Jeyabalan
authors.initials: J
authors.lastname: Nallathambi
authors.forename: Guruswamy
authors.initials: G
authors.lastname: Neethirajan
authors.forename: Shetty
authors.initials: S
authors.lastname: Shashikant
authors.forename: Perumalsamy
authors.initials: P
authors.lastname: Vijayalakshmi
authors.forename: Periasamy
authors.initials: P
authors.lastname: Sundaresan
mesh_terms: D000293:Adolescent; D000409:Alanine; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D000013:Congenital Abnormalities / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005998:Glycine; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007194:India; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D009900:Optic Nerve / Q000002:abnormalities*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D000409:Alanine; D005998:Glycine