title: Screening glaucoma genes in adult glaucoma suggests a multiallelic contribution of CYP1B1 to open-angle glaucoma phenotypes.
abstract: BACKGROUND
  Despite increasing knowledge of the genetic pathophysiology of glaucoma, mutations in known genes account for less than 15% of disease. Gene screening predominantly remains a research tool rather than an essential part of the clinical work-up. We aimed to determine the mutational spectrum and frequency in the genes implicated in glaucoma, in a range of glaucoma and 'glaucoma suspect' (GS) participants, with a positive family history.
  
  
  METHODS
  Observational large case series. One hundred fifteen patients recruited from public hospital and private clinics had diagnoses of GS, ocular hypertension, pseudoexfoliative glaucoma (PXG) or primary open-angle glaucoma (POAG), and at least one affected family member. In a university laboratory, DNA samples were screened for mutations in all coding exons of MYOC and CYP1B1, and OPTN (exons 4, 5 and 16). WDR36 (exons 1, 4, 5, 8, 11, 13 and 17) was screened in those with CYP1B1 changes. LOXL1 risk variants were screened in PXG pedigrees. Cascade screening of family members was undertaken.
  
  
  RESULTS
  Seven out of one hundred fifteen (6.1%) individuals had at least one pathogenic or hypomorphic CYP1B1 allele associated with GS, POAG (5) and PXG phenotypes, including two novel sequence variations (p.Ser6Gly, p.Val243Leu). No pathogenic MYOC change was detected. Five individuals (4.3%) carried an OPTN sequence variation. Three of the seven with CYP1B1 changes had polygenic changes.
  
  
  CONCLUSIONS
  Mutational analysis of known glaucoma genes in a mixed glaucoma population replicates the reported frequency of pathogenic CYP1B1 changes. Heterozygous CYP1B1 changes occurred at a greater frequency than other genes. Glaucoma pathogenesis in the clinic setting is genetically heterogeneous and may be polygenic.
authors: Department of Ophthalmology, Faculty of Medical and Health Sciences, New Zealand National Eye Centre, University of Auckland, Auckland, New Zealand.
authors: Hussain Y
authors: HY
authors: Patel
authors: Amanda J
authors: AJ
authors: Richards
authors: Betina
authors: B
authors: De Karolyi
authors: Stephen J
authors: SJ
authors: Best
authors: Helen V
authors: HV
authors: Danesh-Meyer
authors: Andrea L
authors: AL
authors: Vincent
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000594:Amino Acid Oxidoreductases / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D018797:Cell Cycle Proteins; D065633:Cytochrome P-450 CYP1B1; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D035582:Transcription Factor TFIIIA / Q000235:genetics; D055815:Young Adult; D000099179:Myocilin
chemical_list: D000594:Amino Acid Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D018797:Cell Cycle Proteins; D065633:Cytochrome P-450 CYP1B1; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D035582:Transcription Factor TFIIIA; D000099179:Myocilin; C409460:OPTN protein, human; C502341:WDR36 protein, human; C585496:CYP1B1 protein, human; C445313:LOXL1 protein, human