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

Brodehl A, Dieding M, Klauke B, Dec E, Madaan S, Huang T, Gargus J, Fatima A, Saric T, Cakar H, Walhorn V, et al. (2013)
Circulation: Cardiovascular Genetics 6(6): 615-623.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
Es wurden keine Dateien hochgeladen. Nur Publikationsnachweis!
Brodehl, Andreas; Dieding, Mareike; Klauke, Baerbel; Dec, Eric; Madaan, Shrestha; Huang, Taosheng; Gargus, John; Fatima, Azra; Saric, Tomo; Cakar, Hamdin; Walhorn, VolkerUniBi; Tönsing, KatjaUniBi
Abstract / Bemerkung
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.
desmin; desmosomes; sudden; death; cardiomyopathies; arrhythmias; cardiac; intermediate filaments
Circulation: Cardiovascular Genetics
Page URI


Brodehl A, Dieding M, Klauke B, et al. The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death. Circulation: Cardiovascular Genetics. 2013;6(6):615-623.
Brodehl, A., Dieding, M., Klauke, B., Dec, E., Madaan, S., Huang, T., Gargus, J., et al. (2013). The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death. Circulation: Cardiovascular Genetics, 6(6), 615-623. doi: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., et al. (2013). The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death. Circulation: Cardiovascular Genetics 6, 615-623.
Brodehl, A., et al., 2013. The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death. Circulation: Cardiovascular Genetics, 6(6), p 615-623.
A. Brodehl, et al., “The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death”, Circulation: Cardiovascular Genetics, vol. 6, 2013, pp. 615-623.
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., Anselmetti, D., Christensen, A.H., Kimonis, V., Milting, H.: The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death. Circulation: Cardiovascular Genetics. 6, 615-623 (2013).
Brodehl, Andreas, Dieding, Mareike, Klauke, Baerbel, Dec, Eric, Madaan, Shrestha, Huang, Taosheng, Gargus, John, Fatima, Azra, Saric, Tomo, Cakar, Hamdin, Walhorn, Volker, Tönsing, Katja, Skrzipczyk, Tim, Cebulla, Ramona, Gerdes, Desiree, Schulz, Uwe, Gummert, Jan, Svendsen, Jesper Hastrup, Olesen, Morten Salling, Anselmetti, Dario, Christensen, Alex Horby, Kimonis, Virginia, and Milting, Hendrik. “The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death”. Circulation: Cardiovascular Genetics 6.6 (2013): 615-623.

10 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia.
Bermúdez-Jiménez FJ, Carriel V, Brodehl A, Alaminos M, Campos A, Schirmer I, Milting H, Abril BÁ, Álvarez M, López-Fernández S, García-Giustiniani D, Monserrat L, Tercedor L, Jiménez-Jáimez J., Circulation 137(15), 2018
PMID: 29212896
Molecular insights into cardiomyopathies associated with desmin (DES) mutations.
Brodehl A, Gaertner-Rommel A, Milting H., Biophys Rev 10(4), 2018
PMID: 29926427
Intermediate filaments in cardiomyopathy.
Tsikitis M, Galata Z, Mavroidis M, Psarras S, Capetanaki Y., Biophys Rev 10(4), 2018
PMID: 30027462
Sudden cardiac death in neuromuscular disorders.
Finsterer J, Stöllberger C, Maeztu C., Int J Cardiol 203(), 2016
PMID: 26551884
Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
Brodehl A, Ferrier RA, Hamilton SJ, Greenway SC, Brundler MA, Yu W, Gibson WT, McKinnon ML, McGillivray B, Alvarez N, Giuffre M, Schwartzentruber J, FORGE Canada Consortium, Gerull B., Hum Mutat 37(3), 2016
PMID: 26666891
Complement system modulation as a target for treatment of arrhythmogenic cardiomyopathy.
Mavroidis M, Davos CH, Psarras S, Varela A, C Athanasiadis N, Katsimpoulas M, Kostavasili I, Maasch C, Vater A, van Tintelen JP, Capetanaki Y., Basic Res Cardiol 110(3), 2015
PMID: 25851234
Desmosomes in the heart: a review of clinical and mechanistic analyses.
Patel DM, Green KJ., Cell Commun Adhes 21(3), 2014
PMID: 24754498

53 References

Daten bereitgestellt von Europe PubMed Central.

Intermediate filaments: primary determinants of cell architecture and plasticity.
Herrmann H, Strelkov SV, Burkhard P, Aebi U., J. Clin. Invest. 119(7), 2009
PMID: 19587452
Missense mutations in desmin associated with familial cardiac and skeletal myopathy.
Goldfarb LG, Park KY, Cervenakova L, Gorokhova S, Lee HS, Vasconcelos O, Nagle JW, Semino-Mora C, Sivakumar K, Dalakas MC., Nat. Genet. 19(4), 1998
PMID: 9697706
A dysfunctional desmin mutation in a patient with severe generalized myopathy.
Munoz-Marmol AM, Strasser G, Isamat M, Coulombe PA, Yang Y, Roca X, Vela E, Mate JL, Coll J, Fernandez-Figueras MT, Navas-Palacios JJ, Ariza A, Fuchs E., Proc. Natl. Acad. Sci. U.S.A. 95(19), 1998
PMID: 9736733

Desmin-related myopathy.
van Spaendonck-Zwarts KY, van Hessem L, Jongbloed JD, de Walle HE, Capetanaki Y, van der Kooi AJ, van Langen IM, van den Berg MP, van Tintelen JP., Clin. Genet. 80(4), 2010
PMID: 20718792
Severe muscle disease-causing desmin mutations interfere with in vitro filament assembly at distinct stages.
Bar H, Mucke N, Kostareva A, Sjoberg G, Aebi U, Herrmann H., Proc. Natl. Acad. Sci. U.S.A. 102(42), 2005
PMID: 16217025
Desmin A213V substitution represents a rare polymorphism but not a mutation and is more prevalent in patients with heart dilation of various origins.
Kostareva A, Sjoberg G, Gudkova A, Smolina N, Semernin E, Shlyakhto E, Sejersen T., Acta Myol 30(1), 2011
PMID: 21842594
Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene.
van Tintelen JP, Van Gelder IC, Asimaki A, Suurmeijer AJ, Wiesfeld AC, Jongbloed JD, van den Wijngaard A, Kuks JB, van Spaendonck-Zwarts KY, Notermans N, Boven L, van den Heuvel F, Veenstra-Knol HE, Saffitz JE, Hofstra RM, van den Berg MP., Heart Rhythm 6(11), 2009
PMID: 19879535
Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks.
Otten E, Asimaki A, Maass A, van Langen IM, van der Wal A, de Jonge N, van den Berg MP, Saffitz JE, Wilde AA, Jongbloed JD, van Tintelen JP., Heart Rhythm 7(8), 2010
PMID: 20423733
De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.
Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H., Hum. Mol. Genet. 19(23), 2010
PMID: 20829228
Desmin myopathy with severe cardiomyopathy in a Uruguayan family due to a codon deletion in a new location within the desmin 1A rod domain.
Vernengo L, Chourbagi O, Panuncio A, Lilienbaum A, Batonnet-Pichon S, Bruston F, Rodrigues-Lima F, Mesa R, Pizzarossa C, Demay L, Richard P, Vicart P, Rodriguez MM., Neuromuscul. Disord. 20(3), 2010
PMID: 20133133
Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation.
Hedberg C, Melberg A, Kuhl A, Jenne D, Oldfors A., Eur. J. Hum. Genet. 20(9), 2012
PMID: 22395865
Desmin mutations and arrhythmogenic right ventricular cardiomyopathy.
Lorenzon A, Beffagna G, Bauce B, De Bortoli M, Li Mura IE, Calore M, Dazzo E, Basso C, Nava A, Thiene G, Rampazzo A., Am. J. Cardiol. 111(3), 2012
PMID: 23168288
Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a review and update.
Azaouagh A, Churzidse S, Konorza T, Erbel R., Clin Res Cardiol 100(5), 2011
PMID: 21360243
Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.
Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L., Nat. Genet. 36(11), 2004
PMID: 15489853
Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy.
Heuser A, Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, MacRae CA, Gerull B., Am. J. Hum. Genet. 79(6), 2006
PMID: 17186466
Homozygous founder mutation in desmocollin-2 (DSC2) causes arrhythmogenic cardiomyopathy in the Hutterite population.
Gerull B, Kirchner F, Chong JX, Tagoe J, Chandrasekharan K, Strohm O, Waggoner D, Ober C, Duff HJ., Circ Cardiovasc Genet 6(4), 2013
PMID: 23863954
Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy.
Elliott P, O'Mahony C, Syrris P, Evans A, Rivera Sorensen C, Sheppard MN, Carr-White G, Pantazis A, McKenna WJ., Circ Cardiovasc Genet 3(4), 2010
PMID: 20716751
Functional characterization of desmin mutant p.P419S.
Brodehl A, Dieding M, Cakar H, Klauke B, Walhorn V, Gummert J, Anselmetti D, Milting H., Eur. J. Hum. Genet. 21(6), 2012
PMID: 23032110
HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte.
Claycomb WC, Lanson NA Jr, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, Izzo NJ Jr., Proc. Natl. Acad. Sci. U.S.A. 95(6), 1998
PMID: 9501201
Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants.
Brodehl A, Hedde PN, Dieding M, Fatima A, Walhorn V, Gayda S, Saric T, Klauke B, Gummert J, Anselmetti D, Heilemann M, Nienhaus GU, Milting H., J. Biol. Chem. 287(19), 2012
PMID: 22403400
In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells.
Fatima A, Xu G, Shao K, Papadopoulos S, Lehmann M, Arnaiz-Cot JJ, Rosa AO, Nguemo F, Matzkies M, Dittmann S, Stone SL, Linke M, Zechner U, Beyer V, Hennies HC, Rosenkranz S, Klauke B, Parwani AS, Haverkamp W, Pfitzer G, Farr M, Cleemann L, Morad M, Milting H, Hescheler J, Saric T., Cell. Physiol. Biochem. 28(4), 2011
PMID: 22178870
Exploring the mechanical behavior of single intermediate filaments.
Kreplak L, Bar H, Leterrier JF, Herrmann H, Aebi U., J. Mol. Biol. 354(3), 2005
PMID: 16257415
Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria.
Quarta G, Muir A, Pantazis A, Syrris P, Gehmlich K, Garcia-Pavia P, Ward D, Sen-Chowdhry S, Elliott PM, McKenna WJ., Circulation 123(23), 2011
PMID: 21606390
Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy.
den Haan AD, Tan BY, Zikusoka MN, Llado LI, Jain R, Daly A, Tichnell C, James C, Amat-Alarcon N, Abraham T, Russell SD, Bluemke DA, Calkins H, Dalal D, Judge DP., Circ Cardiovasc Genet 2(5), 2009
PMID: 20031617
A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies.
Cetin N, Balci-Hayta B, Gundesli H, Korkusuz P, Purali N, Talim B, Tan E, Selcen D, Erdem-Ozdamar S, Dincer P., J. Med. Genet. 50(7), 2013
PMID: 23687351
Exome analysis of two limb-girdle muscular dystrophy families: mutations identified and challenges encountered.
McDonald KK, Stajich J, Blach C, Ashley-Koch AE, Hauser MA., PLoS ONE 7(11), 2012
PMID: 23155419
Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy.
McLaughlin HM, Kelly MA, Hawley PP, Darras BT, Funke B, Picker J., BMC Med. Genet. 14(), 2013
PMID: 23815709
On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria.
Schroder R, Goudeau B, Simon MC, Fischer D, Eggermann T, Clemen CS, Li Z, Reimann J, Xue Z, Rudnik-Schoneborn S, Zerres K, van der Ven PF, Furst DO, Kunz WS, Vicart P., Hum. Mol. Genet. 12(6), 2003
PMID: 12620971
Recessive desmin-null muscular dystrophy with central nuclei and mitochondrial abnormalities.
Henderson M, De Waele L, Hudson J, Eagle M, Sewry C, Marsh J, Charlton R, He L, Blakely EL, Horrocks I, Stewart W, Taylor RW, Longman C, Bushby K, Barresi R., Acta Neuropathol. 125(6), 2013
PMID: 23575897
A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy.
Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE., N. Engl. J. Med. 360(11), 2009
PMID: 19279339
Two related Dutch families with a clinically variable presentation of cardioskeletal myopathy caused by a novel S13F mutation in the desmin gene.
Bergman JE, Veenstra-Knol HE, van Essen AJ, van Ravenswaaij CM, den Dunnen WF, van den Wijngaard A, van Tintelen JP., Eur J Med Genet 50(5), 2007
PMID: 17720647
Characterization of the head-to-tail overlap complexes formed by human lamin A, B1 and B2 "half-minilamin" dimers.
Kapinos LE, Schumacher J, Mucke N, Machaidze G, Burkhard P, Aebi U, Strelkov SV, Herrmann H., J. Mol. Biol. 396(3), 2009
PMID: 20004208
Characterization of the Hydra lamin and its gene: A molecular phylogeny of metazoan lamins.
Erber A, Riemer D, Hofemeister H, Bovenschulte M, Stick R, Panopoulou G, Lehrach H, Weber K., J. Mol. Evol. 49(2), 1999
PMID: 10441677
History and phylogeny of intermediate filaments: now in insects.
Herrmann H, Strelkov SV., BMC Biol. 9(), 2011
PMID: 21356127
Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients.
Bolling MC, Lemmink HH, Jansen GH, Jonkman MF., Br. J. Dermatol. 164(3), 2011
PMID: 21375516
Novel keratin 5 and 14 gene mutations in patients with epidermolysis bullosa simplex from Poland.
Hamada T, Kawano Y, Szczecinska W, Wozniak K, Yasumoto S, Kowalewski C, Hashimoto T., Arch. Dermatol. Res. 296(12), 2005
PMID: 15827748
An alanine to proline mutation in the 1A rod domain of the keratin 10 chain in epidermolytic hyperkeratosis.
Yang JM, Yoneda K, Morita E, Imamura S, Nam K, Lee ES, Steinert PM., J. Invest. Dermatol. 109(5), 1997
PMID: 9347802
Heterozygous Ala137Pro mutation in keratin 12 gene found in Japanese with Meesmann's corneal dystrophy.
Takahashi K, Takahashi K, Murakami A, Okisaka S, Kimura T, Kanai A., Jpn. J. Ophthalmol. 46(6), 2002
PMID: 12543196
A novel missense mutation, A118E, in the helix initiation motif of the type II hair cortex keratin hHb6, causing monilethrix.
Winter H, Vabres P, Larregue M, Rogers MA, Schweizer J., Hum. Hered. 50(5), 2000
PMID: 10878478
Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.
Brown CA, Lanning RW, McKinney KQ, Salvino AR, Cherniske E, Crowe CA, Darras BT, Gominak S, Greenberg CR, Grosmann C, Heydemann P, Mendell JR, Pober BR, Sasaki T, Shapiro F, Simpson DA, Suchowersky O, Spence JE., Am. J. Med. Genet. 102(4), 2001
PMID: 11503164
New insights into the molecular basis of desmoplakin- and desmin-related cardiomyopathies.
Lapouge K, Fontao L, Champliaud MF, Jaunin F, Frias MA, Favre B, Paulin D, Green KJ, Borradori L., J. Cell. Sci. 119(Pt 23), 2006
PMID: 17105773
Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects.
Arbustini E, Pasotti M, Pilotto A, Pellegrini C, Grasso M, Previtali S, Repetto A, Bellini O, Azan G, Scaffino M, Campana C, Piccolo G, Vigano M, Tavazzi L., Eur. J. Heart Fail. 8(5), 2005
PMID: 16376610
Connexin expression patterns in arrhythmogenic right ventricular cardiomyopathy.
Paul M, Wichter T, Gerss J, Arps V, Schulze-Bahr E, Robenek H, Breithardt G, Weissen-Plenz G., Am. J. Cardiol. 111(10), 2013
PMID: 23465095
Site-directed spin labeling and electron paramagnetic resonance determination of vimentin head domain structure.
Aziz A, Hess JF, Budamagunta MS, Voss JC, Fitzgerald PG., J. Biol. Chem. 285(20), 2010
PMID: 20231271


Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®


PMID: 24200904
PubMed | Europe PMC

Suchen in

Google Scholar