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J Med Genet. Dec 2004; 41(12): 923–931.
PMCID: PMC1735656
A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions
K Griffin, L Kirschner, L Matyakhina, S Stergiopoulos, A Robinson-White, S Lenherr, F Weinberg, E Claflin, D Batista, I Bourdeau, A Voutetakis, F Sandrini, E Meoli, A Bauer, Y Cho-Chung, S Bornstein, J Carney, and C Stratakis
Section on Genetics & Endocrinology, Developmental Endocrinology Branch (DEB), National Institute of Child Health & Human Development, Bethesda, MD 20892-1103, USA. griffiku@mail.nih.gov <griffiku/at/mail.nih.gov>
Abstract
Background: Inactivation of the human type Iα regulatory subunit (RIα) of cyclic AMP dependent protein kinase (PKA) (PRKAR1A) leads to altered kinase activity, primary pigmented nodular adrenocortical disease (PPNAD), and sporadic adrenal and other tumours.
Methods and results: A transgenic mouse carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline responsive promoter (the Tg(Prkar1a*x2as)1Stra, Tg(tTAhCMV)3Uh or tTA/X2AS line) developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia and other features reminiscent of PPNAD, including late onset weight gain, visceral adiposity, and non-dexamethasone suppressible hypercorticosteronaemia, with histiocytic, epithelial hyperplasias, lymphomas, and other mesenchymal tumours. These lesions were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIß protein levels; the latter biochemical and protein changes were also documented in Carney complex tumours associated with PRKAR1A inactivating mutations and chromosome 17 PRKAR1A locus changes.
Conclusion: We conclude that the tTA/X2AS mouse line with a downregulated Prkar1a gene replicates several of the findings in Carney complex patients and their affected tissues, supporting the role of RIα as a candidate tumour suppressor gene.
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