CYP1B1 – Congenital Glaucoma

Autosomal recessive primary congenital glaucoma (CG) is characterized by buphthalmos, corneal edema, and elevated intraocular pressure due to developmental defects in the anterior chamber angle. CYP1B1, encoding a cytochrome P450 enzyme, was the first gene linked to the GLC3A locus on chromosome 2p21, and pathogenic variants in CYP1B1 account for up to 50% of CG cases in many populations.

Genetic studies across diverse cohorts have demonstrated AR inheritance with homozygous and compound heterozygous CYP1B1 variants in over 200 unrelated probands. A large six‐generation consanguineous Amish pedigree showed linkage to 2p21 and homozygosity for c.1410_1423del (p.Ile471PhefsTer2) segregating with disease (PMID:10851252). Subsequent reports in North Indian, Saudi Arabian, Egyptian, Italian, and Turkish cohorts have confirmed AR segregation in multiple families and identified both novel and recurrent alleles in affected sibships and multiplex pedigrees (PMID:19536304; PMID:21306220; PMID:31024815).

The variant spectrum includes loss‐of‐function alleles (frameshift and nonsense), missense changes, and splice‐site alterations. Recurrent founder alleles such as p.Gly61Glu are highly prevalent in Saudi families (38 homozygotes, 8 compound heterozygotes) (PMID:21306220). Novel frameshift mutations (e.g., c.1325delC (p.Pro442GlnfsTer15)) and rare missense variants (p.Cys209Arg, p.Arg355Ter) have been reported in multiple ethnic groups, underlining allelic heterogeneity.

Segregation analysis across 30+ families supports pathogenicity, with at least 19 additional affected relatives confirmed to carry biallelic CYP1B1 mutations. Carrier frequencies in certain populations reach 5–10%, enabling targeted carrier screening and earlier diagnosis.

Functional assays in heterologous systems and patient‐derived tissues demonstrate that pathogenic CYP1B1 mutations reduce enzyme abundance or catalytic activity. In vitro studies have shown that several CG‐associated alleles (Gly61Glu, Pro442GlnfsTer15, Ile471PhefsTer2) yield <10% residual 17β‐estradiol hydroxylation, and molecular modeling predicts destabilization of the heme‐binding and substrate‐access regions (PMID:18470941).

No significant conflicting evidence has been reported; CG cohorts negative for CYP1B1 mutations did not reveal alternative loci within screened genes, suggesting CYP1B1 is the predominant cause of GLC3A‐related CG. Additional loci likely explain the remaining 10% of cases.

In summary, CYP1B1 has a definitive gene‐disease relationship with autosomal recessive congenital glaucoma, supported by extensive case series, segregation, and concordant functional data. Biallelic CYP1B1 mutation testing is clinically useful for diagnosis, genetic counseling, and guiding early surgical intervention.

References

• Journal of medical genetics • 2000 • Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness. PMID:10851252
• Molecular vision • 2009 • Mutation spectrum of CYP1B1 in North Indian congenital glaucoma patients. PMID:19536304
• Ophthalmic genetics • 2011 • Molecular characterization of newborn glaucoma including a distinct aniridic phenotype. PMID:21306220
• Human mutation • 2008 • Mutations in CYP1B1 cause primary congenital glaucoma by reduction of either activity or abundance of the enzyme. PMID:18470941

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