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

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 duplicat...

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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
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Summary:	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.
ISSN:	0804-4643 1479-683X
DOI:	10.1530/EJE-13-0740