title: Late Diagnosis of POMC Deficiency and In Vitro Evidence of Residual Translation From Allele With c.-11C>A Mutation.
abstract: Loss-of-function mutations in the POMC gene are associated with a syndrome with the characteristics of adrenal insufficiency, obesity, and red hair. We describe here a case of pro-opiomelanocortin (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 unique approach.
  
  
  
  A boy presented in the first year of life with red hair, growth acceleration, moderate obesity, and recurrent cholestasis, which was followed by 2 episodes of hypoglycemia at the ages of 1.5 and 3 years. The diagnosis was suspected at the age of 3.6 years after documentation of undetectable levels of plasma adrenocorticotropic hormone and serum cortisol, after which replacement with hydrocortisone was initiated. Sequencing of the POMC gene revealed compound heterozygosity for c.-11C>A/p.W84X mutations. The p.W84X mutation is predicted to result in a marked truncation of preprohormone. Using a messenger RNA transfection approach followed by an 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.
  
  
  
  The current report provides important information on the natural course of POMC deficiency. In vitro translation studies demonstrated residual translation of the main coding region from an allele with the c.-11C>A mutation, which at least partially explains a relatively late presentation of adrenal insufficiency in the patient.
authors.affiliation: School of Bioengineering and Bioinformatics, and.|Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russian Federation.
authors.forename: Aleksandra S
authors.initials: AS
authors.lastname: Anisimova
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 117977, Russian Federation.
authors.forename: Petr M
authors.initials: PM
authors.lastname: Rubtsov
authors.affiliation: School of Bioengineering and Bioinformatics, and.|Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russian Federation.
authors.forename: Kseniya A
authors.initials: KA
authors.lastname: Akulich
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russian Federation.|Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 117977, Russian Federation.
authors.forename: Sergey E
authors.initials: SE
authors.lastname: Dmitriev
authors.affiliation: Federal State Budgetary Institution Scientific Centre of Children's Health, Moscow 119991, Russian Federation; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Frolova
authors.affiliation: Endocrinology Research Centre, Moscow, 117036, Russian Federation.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tiulpakov
mesh_terms: D000309:Adrenal Insufficiency / Q000175:diagnosis* / Q000235:genetics*; D000483:Alleles; D004252:DNA Mutational Analysis / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D009765:Obesity / Q000175:diagnosis* / Q000235:genetics*; D011333:Pro-Opiomelanocortin / Q000172:deficiency* / Q000235:genetics*; D014176:Protein Biosynthesis
chemical_list: D011333:Pro-Opiomelanocortin