title: LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population.
abstract: Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/Gypsy founder population. Comprehensive sequencing analysis revealed a level of heterogeneity unusual for this population, with five CYP1B1 and one ancestral LTBP2 mutation accounting for ∼70% of patients (25 out of 37) and the remainder still unexplained. Homozygosity for the founder LTBP2 p.R299X mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of p.R299X homozygotes showed variable phenotypes (presumably also underlying pathogenetic mechanisms), wherein PCG proper with primary dysgenesis of the trabecular meshwork, and Marfan syndrome-like zonular disease with ectopia lentis and later onset secondary glaucoma are two extremes. The spectrum manifestations may occur in different combinations and have a different evolution even within the same sibship or a single patient. Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. We provide a population genetics perspective to explain the allelic heterogeneity, comparing the history and geographic distribution of the two major founder mutations--p.R299X/LTBP2 and p.E387K/CYP1B1.
authors.affiliation: Laboratory for Molecular Genetics, Centre for Medical Research, QEII Medical Centre, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Dimitar N
authors.initials: DN
authors.lastname: Azmanov
authors.forename: Stanislava
authors.initials: S
authors.lastname: Dimitrova
authors.forename: Laura
authors.initials: L
authors.lastname: Florez
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cherninkova
authors.forename: Dragomir
authors.initials: D
authors.lastname: Draganov
authors.forename: Bharti
authors.initials: B
authors.lastname: Morar
authors.forename: Rosmawati
authors.initials: R
authors.lastname: Saat
authors.forename: Manel
authors.initials: M
authors.lastname: Juan
authors.forename: Juan I
authors.initials: JI
authors.lastname: Arostegui
authors.forename: Sriparna
authors.initials: S
authors.lastname: Ganguly
authors.forename: Himla
authors.initials: H
authors.lastname: Soodyall
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Chakrabarti
authors.forename: Harish
authors.initials: H
authors.lastname: Padh
authors.forename: Miguel A
authors.initials: MA
authors.lastname: López-Nevot
authors.forename: Violeta
authors.initials: V
authors.lastname: Chernodrinska
authors.forename: Botio
authors.initials: B
authors.lastname: Anguelov
authors.forename: Partha
authors.initials: P
authors.lastname: Majumder
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Angelova
authors.forename: Radka
authors.initials: R
authors.lastname: Kaneva
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
mesh_terms: D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D065633:Cytochrome P-450 CYP1B1; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D018703:Founder Effect; D005828:Genetics, Population; D005901:Glaucoma / Q000151:congenital* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D006178:Romani People / Q000235:genetics*; D014129:Trabecular Meshwork; D014785:Vision, Ocular; D055815:Young Adult
chemical_list: C509035:LTBP2 protein, human; D053779:Latent TGF-beta Binding Proteins; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1