Desmin Mutation Responsible for Idiopathic Dilated Cardiomyopathy

Li, Duanxiang; Tapscoft, Terry; González, Oscar; Burch, Paula E.; Quiñones, Miguel Á.; Zoghbi, William A.; Hill, Reba M.; Bachinski, Linda L.; Mann, Douglas L.; Roberts, Robert

doi:10.1161/01.cir.100.5.461

Cited by 391 publications

(188 citation statements)

References 9 publications

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“…Six members of an AD family bearing the p.Ile451Met mutation in the desmin tail domain developed cardiac failure between the ages of 15 to 37 years. 57 Two living patients, father and son, showed cardiomegaly and diminished left ventricular ejection fraction consistent with DCM. No signs of skeletal myopathy were observed.…”

Section: Cardiomyopathymentioning

confidence: 99%

“…The phenomenon of incomplete penetrance was first established in the DCM 20-032 family in which some but not all p.Ile451Met mutation carriers expressed the cardiomyopathy phenotype. 57 In "family B" with progressive skeletal myopathy and no evidence of cardiac involvement three members carrying the p.Ile451Met mutation were also clinically asymptomatic in their 50s and 60s. 58 …”

Section: Incomplete Penetrancementioning

confidence: 99%

“…99 DCM is characterized by an increased ventricular chamber size and reduced systolic output. 57 RCM results from processes that stiffen the myocardium by infiltration or fibrosis leading to impaired ventricular filling and reduced diastolic volume of either or both ventricles with the cavity size, wall thickness of the ventricles and ejection remaining near normal. 100 Of34 patients with cardiomyopathy in which EchoCG was performed, DCM was diagnosed in 18, RCM in 10 and HCM in 6.…”

Section: Cardiomyopathymentioning

confidence: 99%

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Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

107

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Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neckflexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaBcrystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.

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Section: Cardiomyopathymentioning

confidence: 99%

Section: Incomplete Penetrancementioning

confidence: 99%

Section: Cardiomyopathymentioning

confidence: 99%

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Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

107

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“…Genes underlying IDC have been identified from linkage as well as candidate gene studies, and include those coding for proteins involved in the cytoskeleton (desmin, 5 d-sarcoglycan, 6 dystrophin, 7 desmoplakin 8 and metavinculin 9 ), the Z-disk (muscle LIM protein, 10 a-actinin-2 11 and Cypher/ZASP 12 ), the nuclear envelope (lamin A/C 13 ) and ion conduction (phospholamban, 14 SUR2A 15 and the Na v 1.5 ion channel 16 ). Although genes encoding sarcomeric proteins were traditionally considered to be involved in hypertrophic cardiomyopathy, 17 since 1998 it has also been known that mutations in these genes can cause IDC.…”

Section: Introductionmentioning

confidence: 99%

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

et al. 2009

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We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.

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“…20,[27][28][29][30] The clinical examination, laboratory tests and genetic analyses excluded the coexistence of other disorders including laminopathy or a mitochondrial disease. However, the lack of a muscle biopsy, due to refusal by the patient, does not allow us to conclude unequivocally that her cardiac phenotype is due to the CAV3 mutation.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro

Traverso

Gazzerro

Assereto

et al. 2008

Laboratory Investigation

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Caveolins are the principal protein components of caveolae, invaginations of the plasma membrane involved in cell signaling and trafficking. Caveolin-3 (Cav-3) is the muscle-specific isoform of the caveolin family and mutations in the CAV3 gene lead to a large group of neuromuscular disorders. In unrelated patients, we identified two distinct CAV3 mutations involving the same codon 78. Patient 1, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, shows an autosomal recessive mutation converting threonine to methionine (T78M). Patient 2, affected by isolated familiar hyperCKemia, shows an autosomal dominant mutation converting threonine to lysine (T78K). Cav-3 wild type (WT) and Cav-3 mutations were transiently transfected into Cos-7 cells. Cav-3 WT and Cav-3 T78M mutant localized at the plasma membrane, whereas Cav-3 T78K was retained in a perinuclear compartment. Cav-3 T78K expression was decreased by 87% when compared with Cav-3 WT, whereas Cav-3 T78M protein levels were unchanged. To evaluate whether Cav-3 T78K and Cav-3 T78M mutants behaved with a dominant negative pattern, Cos-7 cells were cotransfected with green fluorescent protein (GFP)-Cav-3 WT in combination with either mutant or WT Cav-3. When cotransfected with Cav-3 WT or Cav-3 T78M, GFP-Cav-3 WT was localized at the plasma membrane, as expected. However, when cotransfected with Cav-3 T78K, GFP-Cav-3 WT was retained in a perinuclear compartment, and its protein levels were reduced by 60%, suggesting a dominant negative action. Accordingly, Cav-3 protein levels in muscles from a biopsy of patient 2 (T78K mutation) were reduced by 80%. In conclusion, CAV3 T78M and T78K mutations lead to distinct disorders showing different clinical features and inheritance, and displaying distinct phenotypes in vitro.

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Desmin Mutation Responsible for Idiopathic Dilated Cardiomyopathy

Cited by 391 publications

References 9 publications

Intermediate Filament Diseases: Desminopathy

Intermediate Filament Diseases: Desminopathy

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro

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