Genetic characterization of a mouse line with primary aldosteronism.

In an attempt to define novel genetic loci involved in the pathophysiology of primary aldosteronism, a mutagenesis screen after treatment with the alkylating agent N-ethyl-N-nitrosourea was established for the parameter aldosterone. One of the generated mouse lines with hyperaldosteronism was phenotypically and genetically characterized. This mouse line had high aldosterone levels but normal creatinine and urea values. The steroidogenic enzyme expression levels in the adrenal gland did not differ significantly among phenotypically affected and unaffected mice. Upon exome sequencing, point mutations were identified in seven candidate genes (Sspo, Dguok, Hoxaas2, Clstn3, Atm, Tipin and Mapk6). Subsequently, animals were stratified into wild-type and mutated groups according to their genotype for each of these candidate genes. A correlation of their genotypes with the respective aldosterone, aldosterone-to-renin ratio (ARR), urea and creatinine values as well as steroidogenic enzyme expression levels was performed. Aldosterone values were significantly higher in animals carrying mutations in four different genes (Sspo, Dguok, Hoxaas2 and Clstn3) and associated statistically significant adrenal Cyp11b2 overexpression as well as increased ARR was present only in mice with Sspo mutation. In contrast, mutations of the remaining candidate genes (Atm, Tipin and Mapk6) were associated with lower aldosterone values and lower Hsd3b6 expression levels. In summary, these data demonstrate association between the genes Sspo, Dguok, Hoxaas2 and Clstn3 and hyperaldosteronism. Final proofs for the causative nature of the mutations have to come from knock-out and knock-in experiments.

Genetics of Cushing's disease: an update.

INTRODUCTION: Cushing's disease (CD) results from uncontrolled hypercortisolism induced by ACTH-secreting corticotroph adenomas; accordingly, patients diagnosed with CD usually present several comorbidities and an increased risk of mortality. Hypothesis-driven screenings have led to identification of rare alterations in a low number of patients, although the genetic basis underlying CD has remained unclear until recently. Using whole-exome sequencing, recurrent mutations have been reported in the gene coding for the ubiquitin-specific protease 8 (USP8), a protein with deubiquitinase (DUB) activity that modulates the lysosomal turnover of the EGF receptor (EGFR) and other membrane proteins. METHODS: In this review, we summarize the recent genetic findings and discuss the clinical and pathological implications of USP8 deregulation in corticotroph adenomas. CONCLUSIONS: Mutations in USP8 have been identified in 35-62 % of functional sporadic corticotroph adenomas causing Cushing's disease, but not in any other type of pituitary tumor. These mutations are found mostly in adult female patients and lead to an aberrant DUB activation by impairing the regulation of USP8 by members of the 14-3-3 family of proteins. The consequence of this hyperactivation is a longer retention of EGFR at the plasma membrane which promotes an enhanced production of ACTH.