title: Heterogeneity in the molecular basis of ACTH resistance syndrome.
abstract: OBJECTIVE
  ACTH resistance syndromes are rare, autosomal, and genetically heterogeneous diseases that include familial glucocorticoid deficiency (FGD) and triple A syndrome. FGD has been shown to segregate with mutations in the gene coding for ACTH receptor (MC2R) or melanocortin 2 receptor accessory protein (MRAP), whereas mutations in the triple A syndrome (AAAS, Allgrove syndrome) gene have been found in segregation with triple A syndrome. We describe the clinical findings and molecular analysis of MC2R, MRAP, and AAAS genes in five Brazilian patients with ACTH resistance syndrome.
  
  
  METHODS
  Genomic DNA from patients and their unaffected relatives was extracted from peripheral blood leucocytes and amplified by PCR, followed by automated sequencing. Functional analysis was carried out using Y6 cells expressing wild-type and mutant MC2R.
  
  
  RESULTS
  All five patients showed low cortisol and elevated plasma ACTH levels. One patient had achalasia and alacrima, besides the symptoms of adrenal insufficiency. The molecular analysis of FGD patients revealed a novel p.Gly116Val mutation in the MC2R gene in one patient and p.Met1Ile mutation in the MRAP gene in another patient. Expression of p.Gly116Val MC2R mutant in Y6 cells revealed that this variant failed to stimulate cAMP production. The analysis of the AAAS gene in the patient with triple A syndrome showed a novel g.782_783delTG deletion. The molecular analysis of DNA from other two patients showed no mutation in MC2R, MRAP, or AAAS gene.
  
  
  CONCLUSIONS
  In conclusion, the molecular basis of ACTH resistance syndrome is heterogeneous, segregating with genes coding for proteins involved with ACTH receptor signaling/expression or adrenal gland development and other unknown genes.
authors.affiliation: Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, 14049-900 Sao Paulo, Brazil.
authors.forename: Cristhianna Viesti Advincula
authors.initials: CV
authors.lastname: Collares
authors.forename: Jose
authors.initials: J
authors.lastname: Antunes-Rodrigues
authors.forename: Ayrton Custodio
authors.initials: AC
authors.lastname: Moreira
authors.forename: Suzana Nesi
authors.initials: SN
authors.lastname: Franca
authors.forename: Luiz Alberto
authors.initials: LA
authors.lastname: Pereira
authors.forename: Maria Marta Sarquis
authors.initials: MM
authors.lastname: Soares
authors.forename: Jorge
authors.initials: J
authors.lastname: Elias Junior
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Clark
authors.forename: Margaret
authors.initials: M
authors.lastname: de Castro
authors.forename: Lucila Leico Kagohara
authors.initials: LL
authors.lastname: Elias
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000097:blood / Q000235:genetics* / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D001938:Brazil; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics*; D013577:Syndrome
chemical_list: C416506:AAAS protein, human; C458099:MRAP protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D044103:Receptor, Melanocortin, Type 2; D000324:Adrenocorticotropic Hormone