The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy

Brodehl A, Gaertner-Rommel A, Klauke B, Grewe SA, Schirmer I, Peterschroeder A, Faber L, Vorgerd M, Gummert J, Anselmetti D, Schulz U, et al. (2017)
HUMAN MUTATION 38(8): 947-952.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
Es wurden keine Dateien hochgeladen. Nur Publikationsnachweis!
Brodehl, Andreas; Gaertner-Rommel, Anna; Klauke, Baerbel; Grewe, Simon Andre; Schirmer, Ilona; Peterschroeder, Andreas; Faber, Lothar; Vorgerd, Matthias; Gummert, Jan; Anselmetti, DarioUniBi ; Schulz, Uwe; Paluszkiewicz, Lech
Abstract / Bemerkung
Restrictive cardiomyopathy (RCM) is a rare heart disease characterized by diastolic dysfunction and atrial enlargement. The genetic etiology of RCM is not completely known. We identified by a next-generation sequencing panel the novel CRYAB missense mutation c.326A>G, p.D109G in a small family with RCM in combination with skeletal myopathy with an early onset of the disease. CRYAB encodes B-crystallin, a member of the small heat shock protein family, which is highly expressed in cardiac and skeletal muscle. In addition to in silico prediction analysis, our structural analysis of explanted myocardial tissue of a mutation carrier as well as in vitro cell transfection experiments revealed abnormal protein aggregation of mutant B-crystallin and desmin, supporting the deleterious effect of this novel mutation. In conclusion, CRYAB appears to be a novel RCM gene, which might have relevance for the molecular diagnosis and the genetic counseling of further affected families in the future.
B-crystallin; hypertrophic cardiomyopathy; intermediate filaments; restrictive cardiomyopathy; small heat shock proteins
Page URI


Brodehl A, Gaertner-Rommel A, Klauke B, et al. The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy. HUMAN MUTATION. 2017;38(8):947-952.
Brodehl, A., Gaertner-Rommel, A., Klauke, B., Grewe, S. A., Schirmer, I., Peterschroeder, A., Faber, L., et al. (2017). The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy. HUMAN MUTATION, 38(8), 947-952. doi:10.1002/humu.23248
Brodehl, Andreas, Gaertner-Rommel, Anna, Klauke, Baerbel, Grewe, Simon Andre, Schirmer, Ilona, Peterschroeder, Andreas, Faber, Lothar, et al. 2017. “The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy”. HUMAN MUTATION 38 (8): 947-952.
Brodehl, A., Gaertner-Rommel, A., Klauke, B., Grewe, S. A., Schirmer, I., Peterschroeder, A., Faber, L., Vorgerd, M., Gummert, J., Anselmetti, D., et al. (2017). The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy. HUMAN MUTATION 38, 947-952.
Brodehl, A., et al., 2017. The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy. HUMAN MUTATION, 38(8), p 947-952.
A. Brodehl, et al., “The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy”, HUMAN MUTATION, vol. 38, 2017, pp. 947-952.
Brodehl, A., Gaertner-Rommel, A., Klauke, B., Grewe, S.A., Schirmer, I., Peterschroeder, A., Faber, L., Vorgerd, M., Gummert, J., Anselmetti, D., Schulz, U., Paluszkiewicz, L., Milting, H.: The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy. HUMAN MUTATION. 38, 947-952 (2017).
Brodehl, Andreas, Gaertner-Rommel, Anna, Klauke, Baerbel, Grewe, Simon Andre, Schirmer, Ilona, Peterschroeder, Andreas, Faber, Lothar, Vorgerd, Matthias, Gummert, Jan, Anselmetti, Dario, Schulz, Uwe, Paluszkiewicz, Lech, and Milting, Hendrik. “The novel B-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy”. HUMAN MUTATION 38.8 (2017): 947-952.

6 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

Structural and functional consequences of age-related isomerization in α-crystallins.
Lyon YA, Collier MP, Riggs DL, Degiacomi MT, Benesch JLP, Julian RR., J Biol Chem 294(19), 2019
PMID: 30804217
The role of αB-crystallin in skeletal and cardiac muscle tissues.
Dimauro I, Antonioni A, Mercatelli N, Caporossi D., Cell Stress Chaperones 23(4), 2018
PMID: 29190034
A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy.
Schirmer I, Dieding M, Klauke B, Brodehl A, Gaertner-Rommel A, Walhorn V, Gummert J, Schulz U, Paluszkiewicz L, Anselmetti D, Milting H., Mol Genet Genomic Med 6(2), 2018
PMID: 29274115
De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy.
Kiselev A, Vaz R, Knyazeva A, Khudiakov A, Tarnovskaya S, Liu J, Sergushichev A, Kazakov S, Frishman D, Smolina N, Pervunina T, Jorholt J, Sjoberg G, Vershinina T, Rudenko D, Arner A, Sejersen T, Lindstrand A, Kostareva A., Hum Mutat 39(9), 2018
PMID: 29858533
Molecular insights into cardiomyopathies associated with desmin (DES) mutations.
Brodehl A, Gaertner-Rommel A, Milting H., Biophys Rev 10(4), 2018
PMID: 29926427
FLNC (Filamin-C): A New(er) Player in the Field of Genetic Cardiomyopathies.
Brodehl A, Gaertner-Rommel A, Milting H., Circ Cardiovasc Genet 10(6), 2017
PMID: 29212901

42 References

Daten bereitgestellt von Europe PubMed Central.

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
Crystal structures of alpha-crystallin domain dimers of alphaB-crystallin and Hsp20.
Bagneris C, Bateman OA, Naylor CE, Cronin N, Boelens WC, Keep NH, Slingsby C., J. Mol. Biol. 392(5), 2009
PMID: 19646995
Mutations in ABCC6 cause pseudoxanthoma elasticum.
Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, Swart J, Kool M, van Soest S, Baas F, ten Brink JB, de Jong PT., Nat. Genet. 25(2), 2000
PMID: 10835643
Mutation R120G in alphaB-crystallin, which is linked to a desmin-related myopathy, results in an irregular structure and defective chaperone-like function.
Bova MP, Yaron O, Huang Q, Ding L, Haley DA, Stewart PL, Horwitz J., Proc. Natl. Acad. Sci. U.S.A. 96(11), 1999
PMID: 10339554
Multiple molecular architectures of the eye lens chaperone αB-crystallin elucidated by a triple hybrid approach.
Braun N, Zacharias M, Peschek J, Kastenmuller A, Zou J, Hanzlik M, Haslbeck M, Rappsilber J, Buchner J, Weinkauf S., Proc. Natl. Acad. Sci. U.S.A. 108(51), 2011
PMID: 22143763
Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling.
Brodehl A, Belke DD, Garnett L, Martens K, Abdelfatah N, Rodriguez M, Diao C, Chen YX, Gordon PM, Nygren A, Gerull B., PLoS ONE 12(3), 2017
PMID: 28339476
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
Association of the chaperone alphaB-crystallin with titin in heart muscle.
Bullard B, Ferguson C, Minajeva A, Leake MC, Gautel M, Labeit D, Ding L, Labeit S, Horwitz J, Leonard KR, Linke WA., J. Biol. Chem. 279(9), 2003
PMID: 14676215
Small heat shock proteins in redox metabolism: implications for cardiovascular diseases.
Christians ES, Ishiwata T, Benjamin IJ., Int. J. Biochem. Cell Biol. 44(10), 2012
PMID: 22710345
Crystal structure of R120G disease mutant of human αB-crystallin domain dimer shows closure of a groove.
Clark AR, Naylor CE, Bagneris C, Keep NH, Slingsby C., J. Mol. Biol. 408(1), 2011
PMID: 21329698
Desmin and αB-crystallin interplay in the maintenance of mitochondrial homeostasis and cardiomyocyte survival.
Diokmetzidou A, Soumaka E, Kloukina I, Tsikitis M, Makridakis M, Varela A, Davos CH, Georgopoulos S, Anesti V, Vlahou A, Capetanaki Y., J. Cell. Sci. 129(20), 2016
PMID: 27566162
The specificity of the interaction between αB-crystallin and desmin filaments and its impact on filament aggregation and cell viability.
Elliott JL, Der Perng M, Prescott AR, Jansen KA, Koenderink GH, Quinlan RA., Philos. Trans. R. Soc. Lond., B, Biol. Sci. 368(1617), 2013
PMID: 23530264
A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects αB-crystallin structure.
Fichna JP, Potulska-Chromik A, Miszta P, Redowicz MJ, Kaminska AM, Zekanowski C, Filipek S., BBA Clin 7(), 2016
PMID: 27904835
Images in cardiovascular medicine. Giant right atrium in the setting of desmin-related restrictive cardiomyopathy.
Hager S, Mahrholdt H, Goldfarb LG, Goebel HH, Sechtem U., Circulation 113(4), 2006
PMID: 16449718

Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant.
Hesse A, Altland K, Linke RP, Almeida MR, Saraiva MJ, Steinmetz A, Maisch B., Br Heart J 70(2), 1993
PMID: 8038017
BAG3 directly interacts with mutated alphaB-crystallin to suppress its aggregation and toxicity.
Hishiya A, Salman MN, Carra S, Kampinga HH, Takayama S., PLoS ONE 6(3), 2011
PMID: 21423662
Alpha B-crystallin mutation in dilated cardiomyopathy.
Inagaki N, Hayashi T, Arimura T, Koga Y, Takahashi M, Shibata H, Teraoka K, Chikamori T, Yamashina A, Kimura A., Biochem. Biophys. Res. Commun. 342(2), 2006
PMID: 16483541
Solid-state NMR and SAXS studies provide a structural basis for the activation of alphaB-crystallin oligomers.
Jehle S, Rajagopal P, Bardiaux B, Markovic S, Kuhne R, Stout JR, Higman VA, Klevit RE, van Rossum BJ, Oschkinat H., Nat. Struct. Mol. Biol. 17(9), 2010
PMID: 20802487
A de novo mutation of the beta cardiac myosin heavy chain gene in an infantile restrictive cardiomyopathy.
Karam S, Raboisson MJ, Ducreux C, Chalabreysse L, Millat G, Bozio A, Bouvagnet P., Congenit Heart Dis 3(2), 2008
PMID: 18380764
Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes.
Kaski JP, Syrris P, Burch M, Tome-Esteban MT, Fenton M, Christiansen M, Andersen PS, Sebire N, Ashworth M, Deanfield JE, McKenna WJ, Elliott PM., Heart 94(11), 2008
PMID: 18467357
BAG3 myofibrillar myopathy presenting with cardiomyopathy.
Konersman CG, Bordini BJ, Scharer G, Lawlor MW, Zangwill S, Southern JF, Amos L, Geddes GC, Kliegman R, Collins MP., Neuromuscul. Disord. 25(5), 2015
PMID: 25728519
Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing.
Kostareva A, Kiselev A, Gudkova A, Frishman G, Ruepp A, Frishman D, Smolina N, Tarnovskaya S, Nilsson D, Zlotina A, Khodyuchenko T, Vershinina T, Pervunina T, Klyushina A, Kozlenok A, Sjoberg G, Golovljova I, Sejersen T, Shlyakhto E., PLoS ONE 11(9), 2016
PMID: 27662471
Novel HSPB1 mutation causes both motor neuronopathy and distal myopathy.
Lewis-Smith DJ, Duff J, Pyle A, Griffin H, Polvikoski T, Birchall D, Horvath R, Chinnery PF., Neurol Genet 2(6), 2016
PMID: 27830184
A novel alphaB-crystallin mutation associated with autosomal dominant congenital lamellar cataract.
Liu Y, Zhang X, Luo L, Wu M, Zeng R, Cheng G, Hu B, Liu B, Liang JJ, Shang F., Invest. Ophthalmol. Vis. Sci. 47(3), 2006
PMID: 16505043
Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.
Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ., J. Clin. Invest. 111(2), 2003
PMID: 12531876
Restrictive cardiomyopathy and pseudoxanthoma elasticum skin lesions
Musumeci, Journal of Cardiovascular Medicine (Hagerstown, Md.) (), 2014
Restrictive cardiomyopathy in pseudoxanthoma elasticum.
Navarro-Lopez F, Llorian A, Ferrer-Roca O, Betriu A, Sanz G., Chest 78(1), 1980
PMID: 7471831
Infantile restrictive cardiomyopathy resulting from a mutation in the cardiac troponin T gene.
Peddy SB, Vricella LA, Crosson JE, Oswald GL, Cohn RD, Cameron DE, Valle D, Loeys BL., Pediatrics 117(5), 2006
PMID: 16651346
Titin mutation in familial restrictive cardiomyopathy.
Peled Y, Gramlich M, Yoskovitz G, Feinberg MS, Afek A, Polak-Charcon S, Pras E, Sela BA, Konen E, Weissbrod O, Geiger D, Gordon PM, Thierfelder L, Freimark D, Gerull B, Arad M., Int. J. Cardiol. 171(1), 2013
PMID: 24315344
Evidence for troponin C (TNNC1) as a gene for autosomal recessive restrictive cardiomyopathy with fatal outcome in infancy.
Ploski R, Rydzanicz M, Ksiazczyk TM, Franaszczyk M, Pollak A, Kosinska J, Michalak E, Stawinski P, Ziolkowska L, Bilinska ZT, Werner B., Am. J. Med. Genet. A 170(12), 2016
PMID: 27604170
Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice.
Rajasekaran NS, Connell P, Christians ES, Yan LJ, Taylor RP, Orosz A, Zhang XQ, Stevenson TJ, Peshock RM, Leopold JA, Barry WH, Loscalzo J, Odelberg SJ, Benjamin IJ., Cell 130(3), 2007
PMID: 17693254
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee., Genet. Med. 17(5), 2015
PMID: 25741868
A novel CRYAB mutation resulting in multisystemic disease.
Sacconi S, Feasson L, Antoine JC, Pecheux C, Bernard R, Cobo AM, Casarin A, Salviati L, Desnuelle C, Urtizberea A., Neuromuscul. Disord. 22(1), 2011
PMID: 21920752
Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).
Schulz V, Hendig D, Henjakovic M, Szliska C, Kleesiek K, Gotting C., Hum. Mutat. 27(8), 2006
PMID: 16835894
Inherited cardiomyopathies.
Towbin JA., Circ. J. 78(10), 2014
PMID: 25186923
A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy.
Vicart P, Caron A, Guicheney P, Li Z, Prevost MC, Faure A, Chateau D, Chapon F, Tome F, Dupret JM, Paulin D, Fardeau M., Nat. Genet. 20(1), 1998
PMID: 9731540
Novel phenotype-genotype correlations of restrictive cardiomyopathy with myosin-binding protein C (MYBPC3) gene mutations tested by next-generation sequencing
Wu, Journal of the American Heart Association 4(7), 2015
A novel P20R mutation in the alpha-B crystallin gene causes autosomal dominant congenital posterior polar cataracts in a Chinese family.
Xia XY, Wu QY, An LM, Li WW, Li N, Li TF, Zhang C, Cui YX, Li XJ, Xue CY., BMC Ophthalmol 14(), 2014
PMID: 25195561

Markieren/ Markierung löschen
Markierte Publikationen

Open Data PUB

Web of Science

Dieser Datensatz im Web of Science®

PMID: 28493373
PubMed | Europe PMC

Suchen in

Google Scholar