A naturally occurring loss-of-function human phospholamban mutation (PLN-L39stop) caused lethal dilated cardiomyopathy in homozygous individuals, contrasting with the benign phenotype observed in mice.
Observational (n=106)
No
Does a loss-of-function mutation in the phospholamban (PLN) gene cause dilated cardiomyopathy in humans?
A naturally occurring loss-of-function mutation in human phospholamban causes lethal dilated cardiomyopathy, revealing a critical species difference compared to the benign phenotype observed in PLN-null mice.
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.
Haghighi et al. (2003) conducted an observational in Dilated cardiomyopathy (n=106). PLN-L39stop mutation vs. Wild-type PLN was evaluated on Development of dilated cardiomyopathy and heart failure. A naturally occurring loss-of-function human phospholamban mutation (PLN-L39stop) caused lethal dilated cardiomyopathy in homozygous individuals, contrasting with the benign phenotype observed in mice.