title: Mutation spectrum of FOXC1 and clinical genetic heterogeneity of Axenfeld-Rieger anomaly in India.
abstract: OBJECTIVE
  Axenfeld-Rieger anomaly (ARA) is a form of anterior segment dysgenesis of the eye, mainly caused by mutations in the FOXC1 gene. We had earlier reported a novel mutation in the wing region of FOXC1 in an autosomal dominant family. The present study was aimed to identify the spectrum of mutations in the FOXC1 gene in a cohort of Indian ARA patients from different ethnic backgrounds, and to understand its role in the disease pathogenesis.
  
  
  METHODS
  Two new autosomal dominant families and seven sporadic cases of ARA from different ethnic backgrounds were screened for mutations by direct sequencing of the coding region of the FOXC1 gene. Another autosomal dominant ARA family that was previously reported by us was also included for comparative analysis of clinical genetic parameters. The segregation of the mutations in the autosomal dominant families was analyzed by haplotype and restriction analysis. Genotype-phenotype correlation were also undertaken to study the role of FOXC1 in phenotypic manifestation in the patient cohort.
  
  
  RESULTS
  Three of the nine ARA cases harbored mutations in FOXC1, of which two novel nonsense mutations Q2X and Q123X, resulted in haploinsufficiency of the gene product. The missense mutation (M161K) that we previously reported in an autosomal dominant family was also found in another family. Haplotype analysis of these two families suggested multiple founders in the same ethnic group. The mutations resulted in variable expressions of phenotype among the patients as assessed from their prognosis based on visual outcomes.
  
  
  CONCLUSIONS
  Significant genetic heterogeneity of FOXC1 was observed in a multi-ethnic population studied in this region of India resulting in variable ARA phenotypes. The different visual outcome seen in the patients suggest a variable expression of FOXC1 and also provide some insight for understanding the gene functions in this population.
authors.affiliation: Brien Holden Eye Research Centre, Hyderabad Eye Research Foundation, Hyderabad, India.
authors.forename: Sreelatha
authors.initials: S
authors.lastname: Komatireddy
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Mandal
authors.forename: Aramati Bindu Madhava
authors.initials: AB
authors.lastname: Reddy
authors.forename: Srirangan
authors.initials: S
authors.lastname: Sampath
authors.forename: Shirly George
authors.initials: SG
authors.lastname: Panicker
authors.forename: Dorairajan
authors.initials: D
authors.lastname: Balasubramanian
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000869:Anterior Eye Segment / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D003315:Cornea / Q000002:abnormalities; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005124:Eye Abnormalities / Q000208:ethnology / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors; D018740:Genetic Heterogeneity; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007194:India; D007223:Infant; D007231:Infant, Newborn; D007429:Intraocular Pressure / Q000235:genetics; D007498:Iris / Q000002:abnormalities*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D014157:Transcription Factors