PAX2 – Renal Coloboma Syndrome

PAX2 (HGNC:8616) is a paired-box transcription factor essential for kidney and optic nerve development. Heterozygous PAX2 mutations cause autosomal dominant Renal Coloboma Syndrome (MONDO:0007352), characterized by optic disc coloboma and renal hypoplasia or dysplasia. Clinical presentations often include vesicoureteral reflux, renal insufficiency and variable ocular anomalies (e.g., optic nerve excavation) (PMID:9760197).

Genetic studies have identified PAX2 pathogenic variants in at least 173 affected individuals from 86 unrelated families, including missense substitutions, truncating frameshifts, splice-site changes, and small duplications (PMID:22213154). Segregation of heterozygous variants with disease in multi-generation pedigrees confirms autosomal dominant inheritance, with variable expressivity but high penetrance of renal or ocular features.

The variant spectrum encompasses c.221_226dup (p.Glu74_Thr75dup), c.226G>A (p.Gly76Ser), c.76dup (p.Val26fs), c.619dup (p.Val207GlyfsTer3) and numerous other coding changes. Recurrent founder mutations in the exon 2 homonucleotide tract (e.g., c.76dup) account for multiple independent cases. Deep intronic and large deletion events are rare; most pathogenic alleles lead to haploinsufficiency.

Functional evidence supports a loss-of-function mechanism. Heterozygous Pax2(1Neu) mice exhibit renal hypoplasia with increased apoptosis of nephron progenitors, mirroring human RCS (PMID:10587573). Three reported missense mutations in the paired domain (including p.Glu74_Thr75dup) act as hypomorphic alleles, reducing transactivation and protein stability in vitro and in vivo (PMID:20221250).

Although isolated ocular colobomas occur without detectable PAX2 variants, such cases lack the renal phenotype and PAX2 mutations are unlikely in isolated coloboma cohorts (PMID:9783702). No studies to date have refuted the core gene–disease relationship.

Integration of genetic and experimental data yields a Definitive association between PAX2 and Renal Coloboma Syndrome. Genetic testing for PAX2 variants enables early diagnosis and family counseling, guiding surveillance for renal impairment and ophthalmologic evaluation.

Key Take-Home: PAX2 haploinsufficiency causes a clinically recognizable autosomal dominant syndrome of renal dysplasia and optic nerve coloboma, with definitive genetic and functional validation.

References

• Human genetics • 1998 • Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330) PMID:9760197
• Human mutation • 2012 • Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database PMID:22213154
• Human molecular genetics • 2000 • Primary renal hypoplasia in humans and mice with PAX2 mutations: evidence of increased apoptosis in fetal kidneys of Pax2(1Neu)+/− mutant mice PMID:10587573
• PLoS genetics • 2010 • Papillorenal syndrome-causing missense mutations in PAX2/Pax2 result in hypomorphic alleles in mouse and human PMID:20221250
• Journal of medical genetics • 1998 • The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies PMID:9783702

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