title: Molecular analysis of the PAX6 gene in Mexican patients with congenital aniridia: report of four novel mutations.
abstract: OBJECTIVE
  Paired box gene 6 (PAX6) heterozygous mutations are well known to cause congenital non-syndromic aniridia. These mutations produce primarily protein truncations and have been identified in approximately 40%-80% of all aniridia cases worldwide. In Mexico, there is only one previous report describing three intragenic deletions in five cases. In this study, we further analyze PAX6 variants in a group of Mexican aniridia patients and describe associated ocular findings.
  
  
  METHODS
  We evaluated 30 nonrelated probands from two referral hospitals. Mutations were detected by single-strand conformation polymorphism (SSCP) and direct sequencing, and novel missense mutations and intronic changes were analyzed by in silico analysis. One intronic variation (IVS2+9G>A), which in silico analysis suggested had no pathological effects, was searched in 103 unaffected controls.
  
  
  RESULTS
  Almost all cases exhibited phenotypes that were at the severe end of the aniridia spectrum with associated ocular alterations such as nystagmus, macular hypoplasia, and congenital cataracts. The mutation detection rate was 30%. Eight different mutations were identified: four (c.184_188dupGAGAC, c.361T>C, c.879dupC, and c.277G>A) were novel, and four (c.969C>T, IVS6+1G>C, c.853delC, and IVS7-2A>G) have been previously reported. The substitution at position 969 was observed in two patients. None of the intragenic deletions previously reported in Mexican patients were found. Most of the mutations detected predict either truncation of the PAX6 protein or conservative amino acid changes in the paired domain. We also detected two intronic non-pathogenic variations, IVS9-12C>T and IVS2+9G>A, that had been previously reported. Because the latter variation was considered potentially pathogenic, it was analyzed in 103 healthy Mexican newborns where we found an allelic frequency of 0.1116 for the A allele.
  
  
  CONCLUSIONS
  This study adds four novel mutations to the worldwide PAX6 mutational spectrum, and reaffirms the finding that c.969C>T is one of the three more frequent causal mutations in aniridia cases. It also provides evidence that IVS2+9G>A is an intronic change without pathogenic effect.
authors.affiliation: Department of Human Genetics, National Institute of Pediatrics, Mexico City, Mexico.
authors.forename: Camilo E
authors.initials: CE
authors.lastname: Villarroel
authors.forename: Cristina
authors.initials: C
authors.lastname: Villanueva-Mendoza
authors.forename: Lorena
authors.initials: L
authors.lastname: Orozco
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Alcántara-Ortigoza
authors.forename: Diana F
authors.initials: DF
authors.lastname: Jiménez
authors.forename: Juan C
authors.initials: JC
authors.lastname: Ordaz
authors.forename: Ariadna
authors.initials: A
authors.lastname: González-del Angel
mesh_terms: D000293:Adolescent; D000328:Adult; D044467:American Indian or Alaska Native / Q000235:genetics*; D015783:Aniridia / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008800:Mexico; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / 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
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