CYP1B1 and Peters Anomaly

Peters anomaly is a rare developmental disorder of the anterior eye segment characterized by central corneal opacity, iridocorneal adhesions, nystagmus, and strabismus ([HP:0000659]; [HP:0007957]; [HP:0011483]; [HP:0000639]; [HP:0000486]). Genetic heterogeneity underlies this condition, with mutations in several transcription factors and structural proteins reported. CYP1B1 (HGNC:2597), classically implicated in primary congenital glaucoma, has emerged as a causative gene for autosomal recessive Peters anomaly in multiple populations.

In a cohort of 11 Peters anomaly patients from 10 Saudi Arabian families, six individuals in five families were homozygous for the missense variant c.182G>A (p.Gly61Glu) and one was homozygous for a 10-bp deletion c.434_443del (p.Arg145fs), accounting for biallelic loss-of-function in 7/11 patients ([PMID:15621878]). No FOXC1, PITX2, or PAX6 mutations were identified in this group, and the phenotype was indistinguishable between CYP1B1-mutant and non-mutant cases. This supports an autosomal recessive inheritance pattern and implicates CYP1B1 in anterior segment dysgenesis.

Screening of 26 unrelated Peters anomaly cases identified six individuals with novel compound heterozygous CYP1B1 changes at codon 432, substituting valine for leucine or arginine, and absent in 100 controls ([PMID:15682044]). Additionally, four CYP1B1 mutations were found in 3/15 Peters anomaly patients (20%), versus 0.7% of controls, reinforcing the gene’s contribution across diverse populations ([PMID:16735991]).

The variant spectrum in Peters anomaly includes missense changes (e.g., p.Gly61Glu, p.Val364Met, p.Arg368His), frameshifts (p.Arg145fs, p.Thr404fs), and small duplications. c.182G>A (p.Gly61Glu) recurs in multiple ethnicities, suggesting a founder or hotspot effect. Biallelic loss-of-function alleles are necessary for disease manifestation, consistent with autosomal recessive transmission.

Functional assays demonstrate that PCG-associated CYP1B1 mutations, including p.Gly61Glu and p.Arg368His, reduce enzymatic activity to <10% of wild type and/or decrease protein stability via accelerated proteasomal degradation ([PMID:18470941]). Structural modeling of mutants predicts disrupted heme binding and altered substrate orientation, concordant with impaired estrogen metabolism and anterior segment development.

Incomplete penetrance has been observed, with nonpenetrant homozygotes identified in two Saudi families ([PMID:15621878]), indicating the influence of modifier loci on phenotypic expression. No studies to date refute CYP1B1’s role in Peters anomaly.

Collectively, genetic and experimental data support a Strong clinical validity for CYP1B1 association with autosomal recessive Peters anomaly, underpinned by >12 probands across ≥10 families, consistent segregation, and concordant loss-of-function functional studies. Key Take-home: Biallelic CYP1B1 loss-of-function variants are a significant cause of Peters anomaly and should be included in diagnostic gene panels for anterior segment dysgenesis.

References

• Ophthalmic genetics • 2004 • Molecular basis of Peters anomaly in Saudi Arabia. PMID:15621878
• Molecular vision • 2005 • A compound heterozygous change found in Peters' anomaly. PMID:15682044
• Molecular vision • 2006 • Further support of the role of CYP1B1 in patients with Peters anomaly. PMID:16735991
• 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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