title: Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees.
abstract: OBJECTIVE
  To determine the possible molecular genetic defect underlying primary congenital glaucoma (PCG) in India and to identify the pathogenic mutations causing this childhood blindness.
  
  
  METHODS
  Twenty-two members of five clinically well-characterized consanguineous families were studied. The primary candidate gene CYP1B1 was amplified from genomic DNA, sequenced, and analyzed in control subjects and patients to identify the disease-causing mutations.
  
  
  RESULTS
  Five distinct mutations were identified in the coding region of CYP1B1 in eight patients of five PCG-affected families, of which three mutations are novel. These include a novel homozygous frameshift, compound heterozygous missense, and other known mutations. One family showed pseudodominance, whereas others were autosomal recessive with full penetrance. In contrast to all known CYP1B1 mutations, the newly identified frameshift is of special significance, because all functional motifs are missing. This, therefore, represents a rare example of a natural functional CYP1B1 knockout, resulting in a null allele (both patients are blind).
  
  
  CONCLUSIONS
  The molecular mechanism leading to the development of PCG is unknown. Because CYP1B1 knockout mice did not show a glaucoma phenotype, the functional knockout identified in this study has important implications in elucidating the pathogenesis of PCG. Further understanding of how this molecular defect leads to PCG could influence the development of specific therapies. This is the first study to describe the molecular basis of PCG from the Indian subcontinent and has profound and multiple clinical implications in diagnosis, genetic counseling, genotype-phenotype correlations and prognosis. Hence, it is a step forward in preventing this devastating childhood blindness.
authors: Hyderabad Eye Research Foundation, L. V. Prasad Eye Institute, L.V. Prasad Marg, Banjara Hills, Hyderabad 500 034, Andhra Pradesh, India. shirly@lvpeye.stph.net
authors: Shirly G
authors: SG
authors: Panicker
authors: Aramati B M
authors: AB
authors: Reddy
authors: Anil K
authors: AK
authors: Mandal
authors: Niyaz
authors: N
authors: Ahmed
authors: Hampapathalu A
authors: HA
authors: Nagarajaram
authors: Seyed E
authors: SE
authors: Hasnain
authors: Dorairajan
authors: D
authors: Balasubramanian
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D002675:Child, Preschool; D003241:Consanguinity; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005902:Glaucoma, Open-Angle / Q000151:congenital* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007194:India / Q000453:epidemiology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D017422:Sequence Analysis, DNA
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1