The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

Andreas Brodehl; Mareike Dieding; Bärbel Klauke; Eric Dec; Shrestha Madaan; Taosheng Huang; John Gargus; Azra Fatima; Tomo Saric; Hamdin Cakar; Volker Walhorn; Katja Tönsing; Tim Skrzipczyk; Ramona Cebulla; Désirée Gerdes; Uwe Schulz; Jan Gummert; Jesper Hastrup Svendsen; Morten Steen Salling Olesen; Dario Anselmetti; Alex Hørby Christensen; Virginia Kimonis; Hendrik Milting

doi:10.1161/CIRCGENETICS.113.000103

The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

Andreas Brodehl, Mareike Dieding, Bärbel Klauke, Eric Dec, Shrestha Madaan, Taosheng Huang, John Gargus, Azra Fatima, Tomo Saric, Hamdin Cakar, Volker Walhorn, Katja Tönsing, Tim Skrzipczyk, Ramona Cebulla, Désirée Gerdes, Uwe Schulz, Jan Gummert, Jesper Hastrup Svendsen, Morten Steen Salling Olesen, Dario AnselmettiAlex Hørby Christensen, Virginia Kimonis, Hendrik Milting

27 Citationer (Scopus)

Abstract

Background-The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known. Methods and Results-We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type. Conclusions-Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.

Originalsprog	Engelsk
Tidsskrift	Circulation. Cardiovascular Genetics (Online)
Vol/bind	6
Udgave nummer	6
Sider (fra-til)	615-623
Antal sider	9
ISSN	1942-3268
DOI	https://doi.org/10.1161/CIRCGENETICS.113.000103
Status	Udgivet - dec. 2013

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10.1161/CIRCGENETICS.113.000103

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Brodehl, A., Dieding, M., Klauke, B., Dec, E., Madaan, S., Huang, T., Gargus, J., Fatima, A., Saric, T., Cakar, H., Walhorn, V., Tönsing, K., Skrzipczyk, T., Cebulla, R., Gerdes, D., Schulz, U., Gummert, J., Svendsen, J. H., Olesen, M. S. S., ... Milting, H. (2013). The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death. Circulation. Cardiovascular Genetics (Online), 6(6), 615-623. https://doi.org/10.1161/CIRCGENETICS.113.000103

Brodehl, A, Dieding, M, Klauke, B, Dec, E, Madaan, S, Huang, T, Gargus, J, Fatima, A, Saric, T, Cakar, H, Walhorn, V, Tönsing, K, Skrzipczyk, T, Cebulla, R, Gerdes, D, Schulz, U, Gummert, J, Svendsen, JH, Olesen, MSS, Anselmetti, D, Christensen, AH, Kimonis, V & Milting, H 2013, 'The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death', Circulation. Cardiovascular Genetics (Online), bind 6, nr. 6, s. 615-623. https://doi.org/10.1161/CIRCGENETICS.113.000103

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title = "The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death",

abstract = "Background-The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known. Methods and Results-We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type. Conclusions-Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.",

author = "Andreas Brodehl and Mareike Dieding and B{\"a}rbel Klauke and Eric Dec and Shrestha Madaan and Taosheng Huang and John Gargus and Azra Fatima and Tomo Saric and Hamdin Cakar and Volker Walhorn and Katja T{\"o}nsing and Tim Skrzipczyk and Ramona Cebulla and D{\'e}sir{\'e}e Gerdes and Uwe Schulz and Jan Gummert and Svendsen, {Jesper Hastrup} and Olesen, {Morten Steen Salling} and Dario Anselmetti and Christensen, {Alex H{\o}rby} and Virginia Kimonis and Hendrik Milting",

year = "2013",

month = dec,

doi = "10.1161/CIRCGENETICS.113.000103",

language = "English",

volume = "6",

pages = "615--623",

journal = "Circulation. Cardiovascular Genetics (Online)",

issn = "1942-3268",

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TY - JOUR

T1 - The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

AU - Brodehl, Andreas

AU - Dieding, Mareike

AU - Klauke, Bärbel

AU - Dec, Eric

AU - Madaan, Shrestha

AU - Huang, Taosheng

AU - Gargus, John

AU - Fatima, Azra

AU - Saric, Tomo

AU - Cakar, Hamdin

AU - Walhorn, Volker

AU - Tönsing, Katja

AU - Skrzipczyk, Tim

AU - Cebulla, Ramona

AU - Gerdes, Désirée

AU - Schulz, Uwe

AU - Gummert, Jan

AU - Svendsen, Jesper Hastrup

AU - Olesen, Morten Steen Salling

AU - Anselmetti, Dario

AU - Christensen, Alex Hørby

AU - Kimonis, Virginia

AU - Milting, Hendrik

PY - 2013/12

Y1 - 2013/12

N2 - Background-The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known. Methods and Results-We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type. Conclusions-Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.

AB - Background-The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known. Methods and Results-We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type. Conclusions-Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.

U2 - 10.1161/CIRCGENETICS.113.000103

DO - 10.1161/CIRCGENETICS.113.000103

M3 - Journal article

C2 - 24200904

SN - 1942-3268

VL - 6

SP - 615

EP - 623

JO - Circulation. Cardiovascular Genetics (Online)

JF - Circulation. Cardiovascular Genetics (Online)

IS - 6

ER -

The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

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