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Anterior gradient 2 (AGR2) is a protein disulfide isomerase crucial for endoplasmic reticulum processing of mucins in the respiratory and gastrointestinal tracts. Bi-allelic AGR2 variants underlie a Mendelian syndrome of recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD; MONDO_0859370), characterized by impaired mucin secretion and barrier dysfunction.
ClinGen classification supports a Moderate gene–disease association based on at least 17 affected individuals from multiple unrelated families ([PMID:39673647]). The condition follows an autosomal recessive inheritance pattern with homozygous missense variants. Evidence includes concordant segregation in a consanguineous pedigree and replication across independent reports.
Genetic evidence (Moderate): A novel homozygous c.250A>C (p.Ser84Arg) variant in AGR2 was identified in two siblings with RIFTD; both parents were heterozygous carriers, confirming segregation under AR inheritance ([PMID:39673647]). Across published cohorts, all reported variants are homozygous missense changes affecting conserved residues in the thioredoxin fold.
Functional evidence (Moderate): Transient overexpression of Ser84Arg AGR2 demonstrated decreased protein stability and enhanced covalent dimerization under non-reducing conditions, disrupting the monomer–dimer equilibrium essential for AGR2 chaperone activity ([PMID:39673647]). Structural modeling corroborated substitution of a conserved CXXS motif with CXXR as the pathogenic mechanism.
No significant conflicting evidence has been reported. The combined genetic and biochemical data delineate a loss-of-function mechanism for AGR2 in mucin maturation, providing a robust basis for molecular diagnosis.
Key Take-home: Homozygous AGR2 missense variants reliably define RIFTD, enabling genetic confirmation and guiding mucin-focused therapeutic strategies.
Gene–Disease AssociationModerate17 probands from multiple unrelated families ([PMID:39673647]), autosomal recessive inheritance, concordant segregation and functional assays Genetic EvidenceModerateBi-allelic homozygous missense AGR2 variants segregate in affected individuals in consanguineous family ([PMID:39673647]) Functional EvidenceModerateBiochemical assays show Ser84Arg destabilizes AGR2 and enhances aberrant dimerization consistent with loss-of-function ([PMID:39673647]) |