Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.
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.
Veugelers
Mark
M
Greenberg Cardiology Division, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Wilkes
David
D
Burton
Kimberly
K
McDermott
Deborah A
DA
Song
Yan
Y
Goldstein
Marsha M
MM
La Perle
Krista
K
Vaughan
Carl J
CJ
O'Hagan
Art
A
Bennett
Kenneth R
KR
Meyer
Beat J
BJ
Legius
Eric
E
Karttunen
Mervi
M
Norio
Reijo
R
Kaariainen
Helena
H
Lavyne
Michael
M
Neau
Jean-Philippe
JP
Richter
Gert
G
Kirali
Kaan
K
Farnsworth
Alan
A
Stapleton
Karen
K
Morelli
Peter
P
Takanashi
Yoshinori
Y
Bamforth
John-Steven
JS
Eitelberger
Franz
F
Noszian
Irene
I
Manfroi
Waldimiro
W
Powers
James
J
Mochizuki
Yoshihiko
Y
Imai
Tsuneo
T
Ko
Gary T C
GT
Driscoll
Deborah A
DA
Goldmuntz
Elizabeth
E
Edelberg
Jay M
JM
Collins
Amanda
A
Eccles
Diana
D
Irvine
Alan D
AD
McKnight
G Stanley
GS
Basson
Craig T
CT
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
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