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PMID:16917092

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Citation

Yang, Z, Bowles, NE, Scherer, SE, Taylor, MD, Kearney, DL, Ge, S, Nadvoretskiy, VV, DeFreitas, G, Carabello, B, Brandon, LI, Godsel, LM, Green, KJ, Saffitz, JE, Li, H, Danieli, GA, Calkins, H, Marcus, F and Towbin, JA (2006) Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ. Res. 99:646-55

Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive degeneration of the right ventricular myocardium, ventricular arrhythmias, fibrous-fatty replacement, and increased risk of sudden death. Mutations in 6 genes, including 4 encoding desmosomal proteins (Junctional plakoglobin (JUP), Desmoplakin (DSP), Plakophilin 2, and Desmoglein 2), have been identified in patients with ARVD/C. Mutation analysis of 66 probands identified 4 variants in DSP; V30M, Q90R, W233X, and R2834H. To establish a cause and effect relationship between those DSP missense mutations and ARVD/C, we performed in vitro and in vivo analyses of the mutated proteins. Unlike wild-type (WT) DSP, the N-terminal mutants (V30M and Q90R) failed to localize to the cell membrane in desomosome-forming cell line and failed to bind to and coimmunoprecipitate JUP. Multiple attempts to generate N-terminal DSP (V30M and Q90R) cardiac-specific transgenes have failed: analysis of embryos revealed evidence of profound ventricular dilation, which likely resulted in embryonic lethality. We were able to develop transgenic (Tg) mice with cardiac-restricted overexpression of the C-terminal mutant (R2834H) or WT DSP. Whereas mice overexpressing WT DSP had no detectable histologic, morphological, or functional cardiac changes, the R2834H-Tg mice had increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid accumulation, along with ventricular enlargement and cardiac dysfunction in both ventricles. These mice also displayed interruption of DSP-desmin interaction at intercalated discs (IDs) and marked ultra-structural changes of IDs. These data suggest DSP expression in cardiomyocytes is crucial for maintaining cardiac tissue integrity, and DSP abnormalities result in ARVD/C by cardiomyocyte death, changes in lipid metabolism, and defects in cardiac development.

Links

PubMed Online version:10.1161/01.RES.0000241482.19382.c6

Keywords

Animals; Apoptosis; Arrhythmogenic Right Ventricular Dysplasia/etiology; Cardiomyopathies/etiology; Cell Communication/genetics; Cell Communication/physiology; Cell Line, Tumor; DNA Mutational Analysis; Desmoplakins/genetics; Desmosomes/genetics; Desmosomes/physiology; Embryo, Mammalian; Heart/growth & development; Humans; Intercellular Junctions/pathology; Lipid Metabolism; Mice; Mice, Transgenic; Mutation, Missense; Myocytes, Cardiac/pathology; Myocytes, Cardiac/ultrastructure

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DESP

involved_in

GO:0003223: ventricular compact myocardium morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DESP

involved_in

GO:0002934: desmosome organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DESP

colocalizes_with

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:DESP

involved_in

GO:0045109: intermediate filament organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DESP

involved_in

GO:0150105: protein localization to cell-cell junction

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P23242)|has_input:(UniProtKB:Q9CQ73)|has_input:(UniProtKB:Q02248)

Seeded From UniProt

complete

HUMAN:PLAK

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P15924

F

Seeded From UniProt

complete

HUMAN:DESP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P14923

F

Seeded From UniProt

complete

HUMAN:DESP

involved_in

GO:0003223: ventricular compact myocardium morphogenesis

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:E9Q557

P

Seeded From UniProt

complete

HUMAN:DESP

involved_in

GO:0002934: desmosome organization

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:E9Q557

P

Seeded From UniProt

complete

HUMAN:DESP

colocalizes_with

GO:0005882: intermediate filament

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:E9Q557

C

Seeded From UniProt

complete

HUMAN:DESP

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DESP

involved_in

GO:0045109: intermediate filament organization

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:E9Q557

P

Seeded From UniProt

complete

HUMAN:DESP

involved_in

GO:0150105: protein localization to cell-cell junction

ECO:0000250: sequence similarity evidence used in manual assertion

UniProtKB:E9Q557

P

Seeded From UniProt

complete

MOUSE:CXA1

located_in

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PLAK

located_in

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:Q9CQ73

located_in

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:DESM

colocalizes_with

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CXA1

part_of

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PLAK

part_of

GO:0005882: intermediate filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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