RBPJ – Adams-Oliver Syndrome

Adams-Oliver syndrome (AOS) is a rare multiple-malformation disorder characterized by aplasia cutis congenita of the vertex scalp (HP:0001057) and transverse terminal limb defects, often accompanied by congenital heart defects in approximately 23% of patients (PMID:28160419). RBPJ encodes the primary transcriptional regulator of the Notch pathway, and heterozygous RBPJ variants have been linked to autosomal dominant AOS. Initial exome sequencing in two independent families identified two unique missense mutations segregating with AOS (c.466A>G (p.Lys156Glu); c.149A>G (p.Glu50Gly)) (PMID:22883147). Follow-up screening in 194 AOS probands revealed three additional RBPJ missense variants, accounting for 2% of cases (PMID:29924900).

In total, five distinct missense variants have been reported in six unrelated probands, with segregation demonstrated in two families (PMID:22883147; PMID:29924900). No recurrent or founder variants have been described. The inheritance pattern is autosomal dominant, and at least four additional affected relatives have been reported to carry pathogenic RBPJ variants.

Functional assays of patient-derived RBPJ variants demonstrate significantly impaired DNA binding compared to wild type, while co-repressor interactions (SMRT/CIR) remain intact, suggesting a dominant-negative mechanism through cofactor sequestration (PMID:22883147). In mammalian two-hybrid and DNA binding assays, mutant RBPJ fails to repress Notch target genes despite preserved cofactor binding, consistent with loss of transcriptional regulation.

A Drosophila Su(H) model harboring an analogous AOS-associated substitution recapitulates developmental defects via cofactor titration, reinforcing the dominant-negative mechanism. Flies with the Su(H) variant exhibit impaired DNA binding without loss of co-activator or co-repressor interaction, leading to Notch target gene dysregulation (PMID:35951645).

No conflicting evidence has been reported that disputes the role of RBPJ in AOS. The genetic and functional data are concordant, establishing a mechanistic link between heterozygous RBPJ missense mutations and AOS phenotypes.

Key take-home: Heterozygous RBPJ missense variants cause autosomal dominant Adams-Oliver syndrome via impaired DNA binding and dominant-negative cofactor sequestration, supporting inclusion of RBPJ in diagnostic gene panels for AOS.

References

• American journal of human genetics • 2012 • RBPJ mutations identified in two families affected by Adams-Oliver syndrome. PMID:22883147
• American journal of medical genetics. Part A • 2017 • Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype. PMID:28160419
• Human mutation • 2018 • Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort. PMID:29924900
• PLoS genetics • 2022 • A Drosophila Su(H) model of Adams-Oliver Syndrome reveals cofactor titration as a mechanism underlying developmental defects. PMID:35951645

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