Primary congenital glaucoma is the most common type of childhood glaucoma, with autosomal recessive inheritance and an incidence ranging from 1 in 30,000 to 1 in 1,250. Signs of the disease include early onset (birth to 3 years ... Primary congenital glaucoma is the most common type of childhood glaucoma, with autosomal recessive inheritance and an incidence ranging from 1 in 30,000 to 1 in 1,250. Signs of the disease include early onset (birth to 3 years of age), increased intraocular pressure, increased corneal diameter, enlarged globe, Haab striae (breaks in Descemet membrane), corneal edema, and optic nerve head cupping. Congenital glaucoma is a chronic disease and a serious cause of blindness worldwide (summary by Azmanov et al., 2011). - Genetic Heterogeneity of Primary Congenital Glaucoma Primary congenital glaucoma-3B (GLC3B; 600975) maps to chromosome 1p36.2-p36.1. GLC3C (613085) maps to chromosome 14q24.3. GLC3D (613086) is caused by mutation in the LTBP2 gene (602091) located on chromosome 14q24 but outside the locus for GLC3C.
The ocular globe is usually large as a result of the increased intraocular pressure dating from intrauterine life, hence the term buphthalmos, meaning 'ox eye.' In only about half of cases are both eyes involved, and males are ... The ocular globe is usually large as a result of the increased intraocular pressure dating from intrauterine life, hence the term buphthalmos, meaning 'ox eye.' In only about half of cases are both eyes involved, and males are affected somewhat more often than females. The canal of Schlemm is present and communicates normally with the veins, as is proved by demonstrable filling of the canal with blood when the jugular veins are compressed. The defect is thought to involve the permeability of the trabeculum to aqueous humor.
Stoilov et al. (1997) used a combination of GLC3A-linked polymorphic markers (STRPs), YAC screening, and radiation hybrid mapping of published and newly generated data on STSs and ESTs to establish a ... - Primary Congenital Glaucoma 3A Stoilov et al. (1997) used a combination of GLC3A-linked polymorphic markers (STRPs), YAC screening, and radiation hybrid mapping of published and newly generated data on STSs and ESTs to establish a critical region that harbors the defective gene in GLC3A. Of 5 potential candidate genes, 1 was placed outside the critical region and another 3 were screened for the presence of coding sequence changes. As a direct result of this screening, they identified 3 different truncating mutations in the human cytochrome P4501B1 gene (601771). A 13-bp deletion (601771.0001) was detected in 1 consanguineous and 1 nonconsanguineous family; a single cytosine insertion (601771.0002) was observed in another 2 consanguineous families; and a large deletion was found in an additional consanguineous family. In 25 Saudi families with primary congenital glaucoma mapping to chromosome 2p21, Bejjani et al. (1998) sequenced the coding exons of CYP1B1 and identified homozygosity or compound heterozygosity for 3 missense mutations (G61E, 601771.0003; R469W, 601771.0006; and D374N, 601771.0007) that segregated with the phenotype in 24 families. Additional clinical and molecular data on some mildly affected relatives showed variable expressivity of PCG in this population, suggesting that genetic and environmental events must modify the effects of CYP1B1 mutations in ocular development. A small number of PCG mutations identified in this Saudi population made both neonatal and population screening attractive public health measures. Following up on their report of 3 distinct CYP1B1 mutations in 24 Saudi families segregating PCG, Bejjani et al. (2000) analyzed 37 additional families and confirmed the initial finding of incomplete penetrance. Eight distinct mutations were identified; the most common Saudi mutations, G61E, R469W, and D374N, accounted for 72%, 12%, and 7%, respectively, of all the PCG chromosomes. Five additional homozygous mutations (2 deletions and 3 missense mutations) were detected, each in a single family. In 22 families, 40 apparently unaffected individuals had mutations and haplotypes identical to their affected sibs. Of these, 2 were subsequently diagnosed with glaucoma and 2 others had abnormal ocular findings consistent with milder forms of glaucoma. Analysis of these 22 kindreds suggested the presence of a dominant modifier locus that is not linked genetically to CYP1B1. In Morocco, Belmouden et al. (2002) studied 32 unrelated patients with primary congenital glaucoma and identified 2 mutations in the CYP1B1 gene in 11 (34%) patients: G61E (601771.0003), previously found in Turkish and Algerian patients, and a 1-bp deletion (4339delG; 601771.0011). Seven patients were homozygous for 4339delG and 2 others for G61E, whereas the remaining 2 were compound heterozygotes. Close association of 4339delG with a rare allele of D2S177, a microsatellite marker located 270 kb upstream of CYP1B1, strongly suggested a founder effect for 4339delG, with the occurrence of the mutation tentatively estimated at between 900 and 1,700 years earlier. In a Spanish patient with primary congenital glaucoma, Lopez-Garrido et al. (2009) identified homozygosity for a mutation (F261L; 601771.0018) in the CYP1B1 gene, which was carried in heterozygous state in her unaffected father but not her mother. Segregation analysis of markers on chromosome 2 was consistent with paternal uniparental isodisomy. In 37 Roma/Gypsy probands with PCG, Azmanov et al. (2011) performed direct sequencing of the entire coding sequence of CYP1B1 as well as exon 4 of the LTBP2 gene (602091), harboring the R299X founder mutation (602091.0001). In 25 (approximately 70%) of the 37 patients, they identified homozygosity or compound heterozygosity for 5 different mutations in CYP1B1, including 4 that had previously been reported as disease-causing in other populations (see, e.g., R368H, 601771.0012 and E387K, 601771.0014) or for the R299X mutation in LTBP2. In 14 patients, no mutation was identified. Homozygosity for the R299X LTBP2 mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. Azmanov et al. (2011) stated that preliminary observations on patients with mutations in both CYP1B1 and LTBP2 suggested that the observed combinations were of no clinical significance and that digenic inheritance was unlikely. Genetic drift was suggested as the 'most plausible scenario' for the allelic heterogeneity seen in this Gypsy population. - Juvenile- and Adult-onset Primary Open Angle Glaucoma In 4 sisters from a Caucasian French family, Melki et al. (2004) identified compound heterozygosity for mutations in the CYP1B1 gene: (G232R, 601771.0013 and E387K, 601771.0014). Two of the sisters had primary congenital glaucoma, whereas the other 2 sisters had adult-onset (ages 35 and 40 years, respectively) primary open angle glaucoma (see 137760). In a French Caucasian family ascertained through a proband who developed juvenile-onset primary open angle glaucoma at the age of 13 years, Melki et al. (2004) identified compound heterozygosity for mutations in the CYP1B1 gene in the proband and in his brother: a 1-bp deletion (3979delA; 601771.0015) and an asn423-to-tyr substitution (N423Y; 601771.0016). The proband's brother had primary congenital glaucoma. The mother carried the N423Y mutation but showed no glaucoma symptoms at the age of 49 years. The father could not be examined. In 2 unrelated French Caucasian patients with adult-onset primary open angle glaucoma, Melki et al. (2004) identified a tyr81-to-asn substitution in the CYP1B1 gene (Y81N; 601771.0017). One of the 2 patients, diagnosed with glaucoma at the age of 52 years, had 2 sons heterozygous for the Y81N mutation who had onset of primary open angle glaucoma at 39 and 44 years of age, respectively. Although PCG-associated CYP1B1 mutations in the heterozygous state had been evaluated for association with POAG in several small studies, their contribution to the occurrence of POAG was uncertain. Pasutto et al. (2010) conducted a study to determine whether heterozygous functionally characterized CYP1B1 mutations were associated with the disease in a large cohort of German patients with POAG (Pasutto et al., 2008). The entire coding region of CYP1B1 was directly sequenced in 399 glaucoma patients (270 with POAG, 47 with JOAG, and 82 with normal-tension glaucoma) and in 376 control subjects. All patients were screened for mutations in the myocilin (MYOC; 601652), optineurin (OPTN; 602432), and WD repeat domain 36 (WDR36; 609669) genes. In vitro functional assays were performed and relative enzymatic activity of the CYP1B1 variants were determined to assess their possible causative role. Apart from known polymorphic variants, Pasutto et al. (2010) identified 11 previously reported amino acid substitutions in CYP1B1 in both PCG and POAG cases. In vitro functional assays demonstrated marked reduction of enzymatic activity for variants P52L (601771.0019) and R368H (601771.0012), confirming their role as loss-of-function mutations. In contrast, 3 other variants showed no relevant effects and were thus classified as polymorphisms. Overall, 7 functionally impaired variants were present in 13 (3.6%) patients and in 1 (0.2%) control subject (P = 0.002). Reanalysis of previous studies reporting CYP1B1 mutations in patients with POAG based on updated functional validation showed a significant excess of carriers among patients compared to controls (P = 2.3 x 10(-7)). Pasutto et al. (2010) concluded that heterozygous CYP1B1 mutations with absent or reduced relative enzymatic activity could be considered a risk factor for POAG. - Digenic Inheritance In a patient with primary congenital glaucoma with onset before 4 months of age, Kaur et al. (2005) identified 2 mutations: 1 in the CYP1B1 gene (601771.0012) and 1 in the MYOC gene (601652.0014). Each of the parents was heterozygous for 1 of the mutations. Kaur et al. (2005) suggested a role for the MYOC gene in primary congenital glaucoma via digenic interactions with other genes.
Chakrabarti et al. (2006) found that common mutations in CYP1B1 that cause primary congenital glaucoma occur on a uniform haplotype background among Indian patients, which is distinct from the modal haplotype background found among unaffected control subjects. They ... Chakrabarti et al. (2006) found that common mutations in CYP1B1 that cause primary congenital glaucoma occur on a uniform haplotype background among Indian patients, which is distinct from the modal haplotype background found among unaffected control subjects. They cited reports of similar findings in other populations, demonstrating strong clustering of CYP1B1 mutations by geographic and haplotype backgrounds. Dimasi et al. (2007) identified 10 different CYP1B1 mutations in 8 (21.6%) of 37 predominantly Caucasian Australian probands with primary congenital glaucoma. The Slovak Rom population is known to have an unusually high frequency of primary congenital glaucoma. Plasilova et al. (1999) reported mutation screening of 43 patients from 26 Slovak Rom (Gypsy) families and identified the same mutation in the CYP1B1 gene in all families (E387K; 601771.0008). The E387K mutation appeared on a common haplotype in all patients, suggesting that it originated from a single ancestral mutational event. Sivadorai et al. (2008) analyzed the CYP1B1 gene in 21 patients from 16 unrelated Bulgarian Gypsy families and detected 5 different mutations. The E387K mutation was detected in only 3 (8%) of 38 mutant alleles, and only 4 (0.56%) of 715 healthy Gypsy controls were heterozygous for the E387K mutation. Sivadorai et al. (2008) concluded that the molecular basis of primary congenital glaucoma in the Gypsy population is unresolved and that diagnostic analysis must extend beyond the E387K mutation.