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

• DOI: 10.1073/pnas.0405535101
• Publication Date: 2004-09-16T00:28:42Z
• Authors: Mark Veugelers; David Wilkes; Kimberly Burton; Deborah A. McDermott; Yan Song; Marsha M. Goldstein; Krista La Perle; Carl J. Vaughan; Art O'Hagan; Kenneth R. Bennett; Beat J. Meyer; Eric Legius; Mervi Karttunen; Reijo Norio; Helena Kaariainen; Michael Lavyne; Jean-Philippe Neau; Gert Richter; Kaan Kirali; Alan Farnsworth; Karen Stapleton; Peter Morelli; Yoshinori Takanashi; John-Steven Bamforth; Franz Eitelberger; Irene Noszian; Waldimiro Manfroi; James Powers; Yoshihiko Mochizuki; Tsuneo Imai; Gary T. C. Ko; Deborah A. Driscoll; Elizabeth Goldmuntz; Jay M. Edelberg; Amanda Collins; Diana Eccles; Alan D. Irvine; G. Stanley McKnight; Craig T. Basson
• Keywords: Haploinsufficiency; Carney Complex; Proband

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