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Comparative PRKAR1A genotype -- phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.

Authors :
Veugeler, Mark
Wilkes, David
Burton, Kimberly
McDermott, Deborah A.
Song, Van
Goldstein, Marsha M.
Perle, Krista La
Vaughan, Carl J.
O'hagan, Art
Bennett, Kenneth R.
Meyer, Beat J.
Legius, Eric
Karttunen, Mervi
Norio, Reijo
Kaariainen, Helena
Lavyne, Michael
Neau, Jean-philippe
Richter, Gert
Kirali, Kaan
Farnsworth, Alan
Source :
Proceedings of the National Academy of Sciences of the United States of America. 9/28/2004, Vol. 101 Issue 39, p14222-14227. 6p.
Publication Year :
2004

Abstract

Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1α of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a+/- mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a+/- mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a+/- mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
101
Issue :
39
Database :
Academic Search Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
14732664
Full Text :
https://doi.org/10.1073/pnas.0405535101