title: Glaucoma phenotype in pedigrees with the myocilin Thr377Met mutation.
abstract: OBJECTIVE
  To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met.
  
  
  METHODS
  Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing.
  
  
  RESULTS
  From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean +/- SD age at diagnosis of 41.2 +/- 11.5 years, and a mean peak intraocular pressure of 31.7 +/- 9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype.
  
  
  CONCLUSIONS
  The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Healey
authors.forename: John H
authors.initials: JH
authors.lastname: Fingert
authors.forename: Michael A
authors.initials: MA
authors.lastname: Coote
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Wong
authors.forename: Colleen H
authors.initials: CH
authors.lastname: Wilkinson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McCartney
authors.forename: Julian L
authors.initials: JL
authors.lastname: Rait
authors.forename: A Pauline
authors.initials: AP
authors.lastname: de Graaf
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
mesh_terms: D000328:Adult; D000368:Aged; D001315:Australia; D003430:Cross-Sectional Studies; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000473:pathology*; D006023:Glycoproteins / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009798:Ocular Hypertension / Q000235:genetics / Q000473:pathology; D009898:Optic Disk / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D014794:Visual Fields; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000099179:Myocilin