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.