PITX2 – Rieger anomaly

PITX2 is a paired-like homeodomain transcription factor critical for anterior segment development. Heterozygous pathogenic variants in PITX2 underlie autosomal-dominant Rieger anomaly, a form of Axenfeld-Rieger malformation characterized by iris hypoplasia, iridocorneal adhesions, and risk of early-onset glaucoma. The gene–disease relationship is supported by multiple independent families and functional analyses demonstrating disrupted DNA binding and transcriptional activity.

Inheritance is autosomal dominant, with full penetrance in reported pedigrees and no reported unaffected carriers. Two unrelated patients with Rieger anomaly were found to harbor a heterozygous missense variant c.350C>G (p.Pro117Arg), which was absent in 100 controls and segregated with disease (PMID:16936096).

Case series and family studies have identified diverse variant classes in Rieger anomaly, including missense, small duplications, and splice-site mutations. In a cohort of 38 unrelated individuals with Axenfeld-Rieger syndrome, three novel homeodomain mutations (e.g., Val45Leu and a 7-amino-acid duplication) were discovered, each absent from controls, confirming allelic heterogeneity (PMID:11487566).

Functional assays demonstrate that PITX2 mutants associated with Rieger anomaly impair DNA binding, transactivation of target genes (e.g., prolactin and PLOD-1), and protein–protein interactions with Pit-1 and MEF2A. Electrophoretic mobility shift assays and reporter studies reveal 2- to >100-fold reductions in activity for homeodomain variants, consistent with a haploinsufficiency or dominant-negative mechanism (PMIDs:9685346, 10958652).

In vivo, transgenic overexpression of wild-type PITX2A in mouse corneal mesenchyme recapitulates ARS-like anterior chamber phenotypes, including corneal opacification and iris defects, whereas T68P and K88E mutants fail to produce abnormalities, underscoring the sensitivity of ocular structures to PITX2 dosage (PMID:15509533).

Collectively, the genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association with Rieger anomaly. PITX2 variant testing provides diagnostic clarity and informs risk assessment for glaucoma.

Key Take-home: Heterozygous PITX2 variants cause dominantly inherited Rieger anomaly via disrupted homeodomain function, guiding molecular diagnosis and management of anterior segment dysgenesis.

References

• Investigative ophthalmology & visual science • 2006 • Novel mutations of FOXC1 and PITX2 in patients with Axenfeld-Rieger malformations. PMID:16936096
• Human molecular genetics • 2000 • Variation in residual PITX2 activity underlies the phenotypic spectrum of anterior segment developmental disorders. PMID:10958652
• The Journal of biological chemistry • 1998 • The molecular basis of Rieger syndrome. Analysis of Pitx2 homeodomain protein activities. PMID:9685346
• The American journal of pathology • 2004 • PITX2 gain-of-function in Rieger syndrome eye model. PMID:15509533

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