A Novel POR G88S Mutation Causes Severe PORD and Establishes a Critical Pharmacogenomic Risk Profile

CONTEXT: P450 oxidoreductase (POR) deficiency is a rare congenital adrenal hyperplasia with variable severity. The mechanisms of severe mutations and their full metabolic consequences, including drug metabolism, are not fully characterized. OBJECTIVE: To define the clinical, biochemical, and molecular consequences of a novel homozygous POR missense mutation, p.Gly88Ser (G88S), identified in 4 unrelated Argentine families. DESIGN: A translational study combining clinical case series analysis with comprehensive in vitro molecular and functional characterization of the novel protein variant. SETTING: Tertiary pediatric endocrine centers in Argentina and Switzerland. PATIENTS: We report 5 individuals (4 46,XY; 1 46,XX) from 4 unrelated families presenting with disorders of sex development and adrenal dysfunction. MAIN OUTCOME MEASURES: Clinical phenotypes, hormonal profiles, and POR gene sequencing. In vitro analysis of recombinant POR measured flavin content, reductase activity, and support of steroidogenic and drug-metabolizing P450s. RESULTS: All patients were homozygous for the c.262G>A (p.G88S) mutation. This FMN binding domain variant caused protein instability with severe loss of FMN (<30%) and FAD (<15%) cofactors. Steroidogenic activities were virtually abolished (CYP21A2: 1.3%; CYP17A1 17,20-lyase: 5.5% of wild-type), explaining the clinical phenotype. Activities of major drug-metabolizing enzymes were also severely impaired (3%-9% of wild-type), establishing a "poor metabolizer" phenotype. CONCLUSION: The POR G88S mutation causes one of the most severe forms of PORD described, driven by dynamic protein instability and cofactor loss. It is a critical pharmacogenomic marker, and its recurrence in Argentina suggests a potential screening target.