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HETEROGENEITY IN THE MOLECULAR BASIS OF ACTH RESISTANCE SYNDROME

C Collares, Department of Physiology, University of Sao Paulo, School of Medicine of Ribeirao Preto, Ribeirao Preto, Brazil
J Antunes-Rodrigues, Department of Physiology, University of Sao Paulo, School of Medicine of Ribeirao Preto, Ribeirao Preto, Brazil
A Moreira, Department of Internal Medicine, University of Sao Paulo, School of Medicine of Ribeirao Preto, Ribeirao Preto, Brazil
S Franca, Department of Pediatrics, Federal University of Parana, Parana, Brazil
L Pereira, Hospital of Santa Maria, Santa Maria, Brazil
M Soares, Department of Internal Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
J Elias Junior, Department of Internal Medicine, University of Sao Paulo, School of Medicine of Ribeirao Preto, Ribeirao Preto, Brazil
A Clark, University of London, Centre for Endocrinology, William Harvey Research Institute, Barts & The London, Queen Mary, London, United Kingdom
M De Castro, Brazil
L Elias, Department of Physiology, University of Sao Paulo, School of Medicine of Ribeirao Preto, Ribeirao Preto, Brazil

Correspondence: Lucila Elias, Email: llelias{at}fmrp.usp.br

Abstract

Objective: Adrenocorticotropin (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 ACTH receptor (MC2R) or MRAP gene, whereas mutations in the AAAS 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.

Design and 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 genes.

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.