title: Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.
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 1alpha 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.
authors.affiliation: Greenberg Cardiology Division, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Veugelers
authors.forename: David
authors.initials: D
authors.lastname: Wilkes
authors.forename: Kimberly
authors.initials: K
authors.lastname: Burton
authors.forename: Deborah A
authors.initials: DA
authors.lastname: McDermott
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.forename: Marsha M
authors.initials: MM
authors.lastname: Goldstein
authors.forename: Krista
authors.initials: K
authors.lastname: La Perle
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Vaughan
authors.forename: Art
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authors.lastname: O'Hagan
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Bennett
authors.forename: Beat J
authors.initials: BJ
authors.lastname: Meyer
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.forename: Mervi
authors.initials: M
authors.lastname: Karttunen
authors.forename: Reijo
authors.initials: R
authors.lastname: Norio
authors.forename: Helena
authors.initials: H
authors.lastname: Kaariainen
authors.forename: Michael
authors.initials: M
authors.lastname: Lavyne
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Neau
authors.forename: Gert
authors.initials: G
authors.lastname: Richter
authors.forename: Kaan
authors.initials: K
authors.lastname: Kirali
authors.forename: Alan
authors.initials: A
authors.lastname: Farnsworth
authors.forename: Karen
authors.initials: K
authors.lastname: Stapleton
authors.forename: Peter
authors.initials: P
authors.lastname: Morelli
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takanashi
authors.forename: John-Steven
authors.initials: JS
authors.lastname: Bamforth
authors.forename: Franz
authors.initials: F
authors.lastname: Eitelberger
authors.forename: Irene
authors.initials: I
authors.lastname: Noszian
authors.forename: Waldimiro
authors.initials: W
authors.lastname: Manfroi
authors.forename: James
authors.initials: J
authors.lastname: Powers
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Mochizuki
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Imai
authors.forename: Gary T C
authors.initials: GT
authors.lastname: Ko
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Driscoll
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
authors.forename: Jay M
authors.initials: JM
authors.lastname: Edelberg
authors.forename: Amanda
authors.initials: A
authors.lastname: Collins
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.forename: G Stanley
authors.initials: GS
authors.lastname: McKnight
authors.forename: Craig T
authors.initials: CT
authors.lastname: Basson
mesh_terms: D000483:Alleles; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases; D004252:DNA Mutational Analysis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009377:Multiple Endocrine Neoplasia / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009232:Myxoma / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; C517835:Prkar1a protein, mouse; D021122:Protein Subunits; D011506:Proteins; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases