Systematic screening for PRKAR1A gene rearrangement in Carney complex: identification and functional characterization of a new in-frame deletion

• Published in: European journal of endocrinology Vol. 170; no. 1; pp. 151 - 160
• Main Authors: Guillaud Bataille, M, Rhayem, Y, Sousa, S B, Libé, R, Dambrun, M, Chevalier, C, Nigou, M, Auzan, C, North, M O, Sa, J, Gomes, L, Salpea, P, Horvath, A, Stratakis, C A, Hamzaoui, N, Bertherat, J, Clauser, E
• Format: Journal Article
• Language: English
• Published: Bristol Bioscientifica Ltd 01-01-2014; BioScientifica
• Subjects: Adolescent; Adrenal Cortex Diseases - genetics; Adrenal Cortex Diseases - metabolism; Adult; Biological and medical sciences; Carney Complex - genetics; Carney Complex - metabolism; Catalytic Domain; Clinical Study; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - chemistry; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - genetics; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - metabolism; Cyclic AMP-Dependent Protein Kinases - chemistry; Cyclic AMP-Dependent Protein Kinases - metabolism; Endocrinopathies; Exons; Family Health; Female; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Rearrangement; Genetic Association Studies; Humans; Male; Medical sciences; Middle Aged; Mutation; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Prevention and actions; Protein Stability; Public health. Hygiene; Public health. Hygiene-occupational medicine; Vertebrates: endocrinology; Young Adult; Endocrinopathy; Characterization; Carney syndrome; Gene rearrangement; Deletion; Digestive diseases; Tumor; Identification; Medical screening; Endocrinology; Carney complex; Genetic disease
• ISSN: 0804-4643; 1479-683X
• DOI: 10.1530/EJE-13-0740

BackgroundPoint mutations of the PRKAR1A gene are a genetic cause of Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD), but in 30% of the patients no mutation is detected.ObjectiveSet up a routine-based technique for systematic detection of large deletions or duplications of this gene and functionally characterize these mutations.MethodsMultiplex ligation-dependent probe amplification (MLPA) of the 12 exons of the PRKAR1A gene was validated and used to detect large rearrangements in 13 typical CNC and 39 confirmed or putative PPNAD without any mutations of the gene. An in-frame deletion was characterized by western blot and bioluminescence resonant energy transfer technique for its interaction with the catalytic subunit.ResultsMLPA allowed identification of exons 3–6 deletion in three patients of a family with typical CNC. The truncated protein is expressed, but rapidly degraded, and does not interact with the protein kinase A catalytic subunit.ConclusionsMLPA is a powerful technique that may be used following the lack of mutations detected by direct sequencing in patients with bona fide CNC or PPNAD. We report here one such new deletion, as an example. However, these gene defects are not a frequent cause of CNC or PPNAD.