Cardiomyopathy, Dilated, 1p

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1P (CMD1P) is caused by heterozygous mutation in the phospholamban gene (PLN; 172405) on chromosome 6q22.

For a discussion of the genetic heterogeneity in hereditary dilated cardiomyopathy, see CMD1A (115200).

Schmitt et al. (2003) reported a 4-generation family with dilated cardiomyopathy (CMD) and heart failure inherited in an autosomal dominant fashion. Affected individuals had increased chamber dimensions and decreased contractile function at age 20 to 30 years, with progression to heart failure within 5 to 10 years after symptom onset. Congestive heart failure was severe in 12 individuals, necessitating cardiac transplantation in 4. The average age at death of affected individuals was 25.1 +/- 12.7 years. Ventricular histopathology demonstrated myocyte enlargement without disarray and extensive interstitial fibrosis.

Schmitt et al. (2003) sequenced the PLN gene in 20 unrelated individuals with inherited dilated cardiomyopathy and heart failure. In 1 individual, a heterozygous arg9-to-cys substitution (R9C; 172405.0001) was identified and segregated with disease over 4 generations of the proband's family.

In 2 unrelated men with idiopathic CMD, Haghighi et al. (2003) identified homozygosity and heterozygosity, respectively, for a truncating mutation of the PLN gene (L39X; 172405.0002). The homozygous man and his homozygous sister developed CMD and heart failure requiring cardiac transplantation at ages 16 and 27 years, respectively. Histopathology of the explanted hearts revealed massive interstitial fibrosis and myofibrillar disarrangement. In the second family, the heterozygous proband and his heterozygous brother had CMD with ejection fractions of 20% and 25%, respectively; their father had died at age 57 of dilated cardiomyopathy. Echocardiographic examination of 9 other heterozygotes from both families revealed incomplete penetrance of the cardiomyopathy phenotype: 4 had left ventricular hypertrophy with normal left ventricular systolic function, and 5 had normal echocardiograms.

In a large pedigree segregating CMD and ventricular arrhythmias, Haghighi et al. (2006) identified heterozygosity for a deletion of arg14 in the PLN gene (172405.0003). The proband was diagnosed at age 50 with heart failure and CMD, and underwent implantation of a cardioverter-defibrillator at age 52 due to episodes of sustained ventricular tachycardia; he continued to have intractable ventricular tachycardia and ventricular fibrillation and died at age 56 while awaiting cardiac transplantation. His brother was diagnosed with CMD at age 42 and had frequent episodes of unsustained ventricular tachycardia; a distant cousin was also diagnosed with CMD and sustained ventricular tachycardia at age 46, at which time a cardioverter-defibrillator was implanted. Of 9 heterozygotes examined in this family, 3 (aged 62, 56, and 35 years, respectively) had mild left ventricular systolic dysfunction and dilation and frequent ventricular extrasystoles; the other 6, all under age 37, were asymptomatic, indicating that the onset of the disease may be age dependent. Characteristic ECG findings in both symptomatic and asymptomatic carriers included low QRS complex potentials throughout and decreased R-wave amplitude in the precordial leads. History, examination, and screening tests of family members who did not carry the mutation did not reveal any findings of cardiomyopathy.

Haghighi et al. (2008) analyzed the PLN gene in 381 CMD patients and 296 controls with no known cardiomyopathy history and identified a heterozygous -36A-C variant in the PLN promoter region (172405.0006) in 22 CMD patients and 1 control. Functional analysis demonstrated that the -36A-C variant increased PLN activity by 24% compared to wildtype and that this alteration in the steroid receptor sequence for the glucocorticoid nuclear receptor/transcription factor resulted in enhanced binding. The PLN -36A-C variant carriers presented with symptoms of heart failure and were diagnosed with cardiomyopathy at ages ranging from 18 years to 44 years. Echocardiography studies indicated severe left ventricular dilatation and systolic dysfunction; some patients' function deteriorated, leading to the death of 1 patient at 48 years of age and heart transplantation in another at 46 years of age. Haghighi et al. (2008) suggested that this variant might contribute to depressed contractility and accelerate functional deterioration in heart failure.