Molecular Genetic and Functional Characterization Implicate Muscle-Restricted Coiled-Coil Gene ( MURC ) as a Causal Gene for Familial Dilated Cardiomyopathy

Abstract

Background Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are classic forms of systolic and diastolic heart failure, respectively. Mutations in genes encoding sarcomere and cytoskeletal proteins are major causes of HCM and DCM. MURC, encoding muscle-restricted coiled-coil, a Z line protein, regulates cardiac function in mice. We investigated potential causal role of MURC in human cardiomyopathies. Methods and Results We sequenced MURC in 1,199 individuals including 383 probands with DCM, 307 with HCM and 509 healthy controls. We found six heterozygous DCM-specific missense variants (p.N128K, p.R140W, p.L153P, p.S307T, p.P324L and p.S364L) in eight unrelated probands. Variants p.N128K and p.S307T segregated with inheritance of DCM in small families (χ2=8.5, p=0.003). Variants p.N128K, p.R140W, p.L153P and p.S364L were considered probably or possibly damaging. Variant p.P324L recurred in three independent probands, including one proband with a TPM1 mutation (p.M245T). A deletion variant (p.L232-R238del) was present in three unrelated HCM probands but it did not segregate with HCM in a family who also had a MYH7 mutation (p.L970V). The phenotype in mutation carriers was notable for progressive heart failure leading to heart transplantation in four patients, conduction defects and atrial arrhythmias. Expression of mutant MURC proteins in neonatal rat cardiac myocytes transduced with recombinant adenoviruses was associated with reduced RhoA activity, lower mRNA levels of hypertrophic markers and smaller myocyte size as compared to wild type MURC. Conclusions MURC mutations impart loss-of-function effects on MURC functions and are likely causal variants in human DCM. The causal role of a deletion mutation in HCM is uncertain.

Caveolae and cancer: A new mechanical perspective

“…Indeed, Cavin4 mutations have recently been linked to human cardiopathies. [48,49] Recent structural studies based on electron microscopy and X-ray crystallography confirm that Cavins together with Cav1 are organizing a caveolar coat that plays an essential role in caveolae assembly. [16][17][18] Thus, it was shown that Cavin1 associated with Cavin2 or Cavin3 in a mutually exclusive manner at a ratio of 2 or 3 to 1 whereas Cavin1 associated with Cav1 at a 1-4 ratio.…”

Loss of MURC/Cavin-4 induces JNK and MMP-9 activity enhancement in vascular smooth muscle cells and exacerbates abdominal aortic aneurysm

“…Mutations in MURC/ Cavin-4 have been identified in patients with dilated cardiomyopathy [20], and the roles of MURC/Cavin-4 in cardiomyocytes have been increasingly uncovered [18,21e23]. MURC/Cavin-4 that is specific to muscle cells is also expressed in VSMCs [18].…”

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

“…MURC activates the Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil-containing protein kinase (ROCK) pathway, increases Anp and regulates myofiber organization. MURC mutations are also considered likely causal variants in human DCM; mutations were associated with progressive HF, conduction defects and cardiac arrhythmias 41 .…”