Late Diagnosis of POMC Deficiency and in vitro evidence of residual translation from allele with c.-11C>A mutation

Context:Loss-of-function mutations in the POMC gene are associated with the syndrome of adrenal insufficiency, obesity and red hair. We describe here a case of POMC deficiency, in which adrenal insufficiency was not treated until the fourth year of life. One of the disease-causative POMC mutations was characterized in vitro using a new approach.Case description:A boy presented in the first year of life with red hair, growth acceleration, moderate obesity and recurrent cholestasis, which was followed by two episodes of hypoglycemia at ages of 1.5 and 3 years. The diagnosis was suspected at the age of 3.6 years after documenting undetectable levels of plasma ACTH and serum cortisol, after which replacement with hydrocortisone was initiated. Sequencing of POMC gene revealed compound heterozygocity for c.-11C>A/p.W84X mutations. p.W84X mutation is predicted to result in a significant truncation of preprohormone. Using an mRNA transfection approach followed by in vitro translation assay we could directly demonstrate that the transcript with c.-11C>A substitution is predominantly translated within a new open reading frame, however translation of the POMC main reading frame is preserved, with translation efficiency being ∼17% of the wild-type transcript.Conclusions:The current description provides important information on the natural course of POMC deficiency. In vitro translation studies demonstrated residual translation of the main coding region from allele with c.-11C>A mutation, which at least partially explains a relatively late presentation of adrenal insufficiency in the patient.