Heterogeneity in the molecular basis of ACTH resistance syndrome.
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.
Collares
Cristhianna Viesti Advincula
CV
Department of Physiology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, 14049-900 Sao Paulo, Brazil.
Antunes-Rodrigues
Jose
J
Moreira
Ayrton Custodio
AC
Franca
Suzana Nesi
SN
Pereira
Luiz Alberto
LA
Soares
Maria Marta Sarquis
MM
Elias Junior
Jorge
J
Clark
Adrian J
AJ
de Castro
Margaret
M
Elias
Lucila Leico Kagohara
LL
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
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