title: Identification of novel CYP1B1 gene mutations in patients with primary congenital and primary open-angle glaucoma.
abstract: BACKGROUND
  CYP1B1 is the most commonly mutated gene in primary congenital glaucoma (PCG), and mutations have also been identified in primary open-angle glaucoma (POAG). This study was undertaken to describe mutations in CYP1B1 in patients and families with PCG and POAG from Pakistan.
  
  
  METHODS
  Case-control series.
  
  
  METHODS
  Forty families, 190 sporadic POAG cases and 140 controls from Pakistan.
  
  
  METHODS
  Patients and healthy individuals of one consanguineous Pakistani family were genotyped with high-resolution single nucleotide polymorphism microarrays. Homozygosity mapping was performed using HomozygosityMapper. Direct sequencing of CYP1B1 gene was performed in probands of the families, sporadic POAG cases and control individuals.
  
  
  METHODS
  Mutations in the CYP1B1 gene in PCG and POAG patients.
  
  
  RESULTS
  Homozygosity mapping in a consanguineous Pakistani family revealed one 11-Mb homozygous region encompassing the CYP1B1 gene. A homozygous CYP1B1 missense mutation (p.Arg390His) was identified in this family. Sequence analysis of CYP1B1 in 39 additional families revealed one known and three novel homozygous mutations in PCG (p.Ala288Pro, p.Asp242Ala, p.Arg355* and p.Arg290Profs*37). In POAG, one novel heterozygous missense mutation (p.Asp316Val) was identified in one family and a previously reported mutation (p.Glu229Lys) was identified in three families. Analysis of CYP1B1 in a panel of 190 sporadic POAG patients revealed three novel heterozygous variants (p.Thr234Lys, p.Ala287Pro and p.Gln362*) and three previously reported heterozygous variants (p.Gly61Glu, p.Glu229Lys and p.Arg368His). The p.Glu229Lys variant was significantly associated with POAG (P = 0.03; odds ratio 2.49).
  
  
  CONCLUSIONS
  This study confirms that CYP1B1 mutations are associated with POAG and PCG in the Pakistani population.
authors.affiliation: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Shazia
authors.initials: S
authors.lastname: Micheal
authors.forename: Humaira
authors.initials: H
authors.lastname: Ayub
authors.forename: Saemah N
authors.initials: SN
authors.lastname: Zafar
authors.forename: Bjorn
authors.initials: B
authors.lastname: Bakker
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ali
authors.forename: Farah
authors.initials: F
authors.lastname: Akhtar
authors.forename: Farrah
authors.initials: F
authors.lastname: Islam
authors.forename: Muhammad I
authors.initials: MI
authors.lastname: Khan
authors.forename: Raheel
authors.initials: R
authors.lastname: Qamar
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002675:Child, Preschool; D003241:Consanguinity; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D005260:Female; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006801:Humans; D006871:Hydrophthalmos / Q000235:genetics*; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1
keywords: cytochrome P4501B1; direct sequencing; homozygosity mapping; primary congenital glaucoma; primary open-angle glaucoma