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Heterogeneity in the molecular basis of ACTH resistance syndrome.

Departments of ¹ , Physiology and ² Internal Medicine, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, 14049-900 Sao Paulo, Brazil³ Department of Pediatrics, University Hospital, Curitiba, Parana, Brazil⁴ Hospital of Santa Maria, Rio Grande do Sul, Brazil⁵ Department of Internal Medicine, School of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil and⁶ William Harvey Research Institute, Centre for Endocrinology, Barts and The London, Queen Mary, University of London, London, UK

(Correspondence should be addressed to L L K Elias who is now at Avenida Bandeirantes, 3900, 14049-900 Ribeirao Preto, Sao Paulo, Brazil; Email: llelias{at}fmrp.usp.br)

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.

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 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.