In human disease and experimental animal models, depressed Ca(2+) handling in 
failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum 
(SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) 
or expression of dominant-negative PLN mutants enhances SR and cardiac function, 
but effects of PLN mutations in humans are unknown. Here, a T116G point 
mutation, substituting a termination codon for Leu-39 (L39stop), was identified 
in two families with hereditary heart failure. The heterozygous individuals 
exhibited hypertrophy without diminished contractile performance. Strikingly, 
both individuals homozygous for L39stop developed dilated cardiomyopathy and 
heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% 
reduction in PLN mRNA and no detectable PLN protein were noted in one explanted 
heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 
293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR 
Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was 
expressed, it was misrouted to the cytosol or plasma membrane. These findings 
describe a naturally-occurring loss-of-function human PLN mutation (PLN null). 
In contrast to reported benefits of PLN ablation in mouse heart failure, humans 
lacking PLN develop lethal dilated cardiomyopathy.