Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system disease.
Mutations in the lamin A/C (LMNA) gene, which encodes nuclear membrane proteins, cause a variety of human conditions including dilated cardiomyopathy (DCM) with associated cardiac conduction system disease. To investigate mechanisms responsible for electrophysiologic and myocardial phenotypes caused by dominant human LMNA mutations, we performed longitudinal evaluations in heterozygous Lmna(+/-) mice. Despite one normal allele, Lmna(+/-) mice had 50% of normal cardiac lamin A/C levels and developed cardiac abnormalities. Conduction system function was normal in neonatal Lmna(+/-) mice but, by 4 weeks of age, atrioventricular (AV) nodal myocytes had abnormally shaped nuclei and active apoptosis. Telemetric and in vivo electrophysiologic studies in 10-week-old Lmna(+/-) mice showed AV conduction defects and both atrial and ventricular arrhythmias, analogous to those observed in humans with heterozygous LMNA mutations. Isolated myocytes from 12-month-old Lmna(+/-) mice exhibited impaired contractility. In vivo cardiac studies of aged Lmna(+/-) mice revealed DCM; in some mice this occurred without overt conduction system disease. However, neither histopathology nor serum CK levels indicated skeletal muscle pathology. These data demonstrate cardiac pathology due to heterozygous Lmna mutations reflecting a 50% reduction in lamin protein levels. Lamin haploinsufficiency caused early-onset programmed cell death of AV nodal myocytes and progressive electrophysiologic disease. While lamin haploinsufficiency was better tolerated by non-conducting myocytes, ultimately, these too succumbed to diminished lamin levels leading to dilated cardiomyopathy, which presumably arose independently from conduction system disease.
Wolf
Cordula M
CM
Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Wang
Libin
L
Alcalai
Ronny
R
Pizard
Anne
A
Burgon
Patrick G
PG
Ahmad
Ferhaan
F
Sherwood
Megan
M
Branco
Dorothy M
DM
Wakimoto
Hiroko
H
Fishman
Glenn I
GI
See
Vincent
V
Stewart
Colin L
CL
Conner
David A
DA
Berul
Charles I
CI
Seidman
Christine E
CE
Seidman
J G
JG
D017668:Age of Onset; D000818:Animals; D017209:Apoptosis; D001145:Arrhythmias, Cardiac / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D001283:Atrioventricular Node / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D002467:Cell Nucleus / Q000473:pathology; D002469:Cell Separation; D004594:Electrophysiology; D006329:Heart Conduction System / Q000201:enzymology / Q000473:pathology*; D006579:Heterozygote; D020287:In Situ Nick-End Labeling; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D009135:Muscular Diseases / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D013686:Telemetry; D014463:Ultrasonography
D034904:Lamin Type A