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.
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References
Sarfarazi M, Stoilov I, Schenkman JB : Genetics and biochemistry of primary congenital glaucoma. Ophthalmol Clin North Am 2003; 16: 543–554.
MacKinnon JR, Giubilato A, Elder JE, Craig JE, Mackey DA : Primary infantile glaucoma in an Australian population. Clin Experiment Ophthalmol 2004; 32: 14–18.
Gencik A, Gencikova A, Ferak V : Population genetical aspects of primary congenital glaucoma. I. Incidence, prevalence, gene frequency, and age of onset. Hum Genet 1982; 61: 193–197.
deLuise VP, Anderson DR : Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol 1983; 28: 1–19.
Ho CL, Walton DS : Primary congenital glaucoma: 2004 update. J Pediatr Ophthalmol Strabismus 2004; 41: 271–288.
Sarfarazi M, Akarsu AN, Hossain A et al: Assignment of a locus (GLC3A) for primary congenital glaucoma (buphthalmos) to 2p21 and evidence for genetic heterogeneity. Genomics 1995; 30: 171–177.
Akarsu AN, Turacli ME, Aktan SG et al.: A second locus (GLC3B) for primary congenital glaucoma (buphthalmos) maps to the 1p36 region. Hum Mol Genet 1996; 5: 1199–1203.
Stoilov I, Sarfarazi M : The third genetic locus (GLC3C) for primary congenital glaucoma (PCG) maps to chromosome 14q24.3. Invest Ophthalmol Vis Sci 2002; 43: 3015.
Plasilova M, Stoilov I, Sarfarazi M, Kadasi L, Ferakova E, Ferak V : Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma. J Med Genet 1999; 36: 290–294.
Kaur K, Reddy AB, Mukhopadhyay A et al: Myocilin gene implicated in primary congenital glaucoma. Clin Genet 2005; 67: 335–340.
Chakrabarti S, Kaur K, Komatireddy S et al: Gln48His is the prevalent myocilin mutation in primary open angle and primary congenital glaucoma phenotypes in India. Mol Vis 2005; 11: 111–113.
Firasat S, Riazuddin SA, Hejtmancik JF, Riazuddin S : Primary congenital glaucoma localizes to chromosome 14q24.2-24.3 in two consanguineous Pakistani families. Mol Vis 2008; 14: 1659–1665.
Ali M, McKibbin M, Booth A et al: Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 2009; 84: 664–671.
Narooie-Nejad M, Paylakhi SH, Shojaee S et al: Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Hum Mol Genet 2009; 18: 3969–3977.
Desir J, Sznajer Y, Depasse F et al: LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma. Eur J Hum Genet 2010; 18: 761–767.
Kumar A, Duvvari MR, Prabhakaran VC, Shetty JS, Murthy GJ, Blanton SH : A homozygous mutation in LTBP2 causes isolated microspherophakia. Hum Genet 2010; 128: 365–371.
Sivadorai P, Cherninkova S, Bouwer S et al: Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in Gypsies. Clin Genet 2008; 74: 82–87.
Kalaydjieva L, Morar B, Chaix R, Tang H : A newly discovered founder population: the Roma/Gypsies. Bioessays 2005; 27: 1084–1094.
Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C : Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009; 37: e67.
Sunyaev S, Ramensky V, Koch I, Lathe III W, Kondrashov AS, Bork P : Prediction of deleterious human alleles. Hum Mol Genet 2001; 10: 591–597.
Barrett JC, Fry B, Maller J, Daly MJ : Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Dimasi DP, Hewitt AW, Straga T et al: Prevalence of CYP1B1 mutations in Australian patients with primary congenital glaucoma. Clin Genet 2007; 72: 255–260.
Stephens M, Smith NJ, Donnelly P : A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.
Reeve JP, Rannala B : DMLE+: Bayesian linkage disequilibrium gene mapping. Bioinformatics 2002; 18: 894–895.
Hunter M, Heyer E, Austerlitz F et al: The P28T mutation in the GALK1 gene accounts for galactokinase deficiency in Roma (Gypsy) patients across Europe. Pediatr Res 2002; 51: 602–606.
Reddy AB, Kaur K, Mandal AK et al: Mutation spectrum of the CYP1B1 gene in Indian primary congenital glaucoma patients. Mol Vis 2004; 10: 696–702.
Panicker SG, Mandal AK, Reddy AB, Gothwal VK, Hasnain SE : Correlations of genotype with phenotype in Indian patients with primary congenital glaucoma. Invest Ophthalmol Vis Sci 2004; 45: 1149–1156.
Chakrabarti S, Kaur K, Kaur I et al: Globally, CYP1B1 mutations in primary congenital glaucoma are strongly structured by geographic and haplotype backgrounds. Invest Ophthalmol Vis Sci 2006; 47: 43–47.
Tanwar M, Dada T, Sihota R, Das TK, Yadav U, Dada R : Mutation spectrum of CYP1B1 in North Indian congenital glaucoma patients. Mol Vis 2009; 15: 1200–1209.
Tremblay M, Vezina H : New estimates of intergenerational time intervals for the calculation of age and origins of mutations. Am J Hum Genet 2000; 66: 651–658.
Gresham D, Morar B, Underhill PA et al: Origins and divergence of the Roma (gypsies). Am J Hum Genet 2001; 69: 1314–1331.
Zlotogora J, Zeigler M, Bach G : Selection in favor of lysosomal storage disorders? Am J Hum Genet 1988; 42: 271–273.
Stoilov I : Cytochrome P450s: coupling development and environment. Trends Genet 2001; 17: 629–632.
Nebert DW, Russell DW : Clinical importance of the cytochromes P450. Lancet 2002; 360: 1155–1162.
Risch N, Tang H, Katzenstein H, Ekstein J : Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection. Am J Hum Genet 2003; 72: 812–822.
Morar B, Gresham D, Angelicheva D et al: Mutation history of the Roma/Gypsies. Am J Hum Genet 2004; 75: 596–609.
Bouwer S, Angelicheva D, Chandler D, Seeman P, Tournev I, Kalaydjieva L : Carrier rates of the ancestral Indian W24X mutation in GJB2 in the general Gypsy population and individual subisolates. Genet Test 2007; 11: 455–458.
RamShankar M, Girirajan S, Dagan O et al: Contribution of connexin26 (GJB2) mutations and founder effect to non-syndromic hearing loss in India. J Med Genet 2003; 40: e68.
Vincent AL, Billingsley G, Buys Y et al: Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 2002; 70: 448–460.
Pasutto F, Chavarria-Soley G, Mardin CY et al: Heterozygous loss of function variants in CYP1B1 predispose to primary open angle glaucoma. Invest Ophthalmol Vis Sci 2010; 51: 249–254.
Lopez-Garrido MP, Blanco-Marchite C, Sanchez-Sanchez F et al: Functional analysis of CYP1B1 mutations and association of heterozygous hypomorphic alleles with primary open-angle glaucoma. Clin Genet 2010; 77: 70–78.
Suri F, Yazdani S, Narooie-Nejhad M et al: Variable expressivity and high penetrance of CYP1B1 mutations associated with primary congenital glaucoma. Ophthalmology 2009; 116: 2101–2109.
Campos-Mollo E, Lopez-Garrido MP, Blanco-Marchite C et al: CYP1B1 mutations in Spanish patients with primary congenital glaucoma: phenotypic and functional variability. Mol Vis 2009; 15: 417–431.
Bagiyeva S, Marfany G, Gonzalez-Angulo O, Gonzalez-Duarte R : Mutational screening of CYP1B1 in Turkish PCG families and functional analyses of newly detected mutations. Mol Vis 2007; 13: 1458–1468.
Dureau P : Pathophysiology of zonular diseases. Curr Opin Ophthalmol 2008; 19: 27–30.
Izquierdo NJ, Traboulsi EI, Enger C, Maumenee IH : Glaucoma in the Marfan syndrome. Trans Am Ophthalmol Soc 1992; 90: 111–117;discussion 118-122.
Whitelaw CM, Anwar S, Ades LC, Gole GA, Elder JE, Savarirayan R : Primary trabeculodysgenesis in association with neonatal Marfan syndrome. Am J Med Genet A 2004; 128A: 418–421.
Acknowledgements
We thank the affected families for their participation. The study is funded by the Australia–India Strategic Research Fund (grant BF020055). DNA is supported by an NHMRC Training Fellowship (634551).
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Azmanov, D., Dimitrova, S., Florez, L. et al. LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. Eur J Hum Genet 19, 326–333 (2011). https://doi.org/10.1038/ejhg.2010.181
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DOI: https://doi.org/10.1038/ejhg.2010.181
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