Startseite Medizin HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy
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HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy

  • Yi-Meng Zhou EMAIL logo , Xiao-Yong Dai , Xing-Biao Qiu , Fang Yuan , Ruo-Gu Li , Ying-Jia Xu , Xin-Kai Qu , Ri-Tai Huang , Song Xue und Yi-Qing Yang EMAIL logo
Veröffentlicht/Copyright: 18. November 2015
Clinical Chemistry and Laboratory Medicine (CCLM)
Aus der Zeitschrift Clinical Chemistry and Laboratory Medicine (CCLM) Band 54 Heft 7

Abstract

Background: The basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown.

Methods: The whole coding region and splicing junctions of the HAND1 gene were sequenced in 140 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 260 unrelated ethnically matched healthy individuals used as controls were genotyped for HAND1. The functional effect of the mutant HAND1 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.

Results: A novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM.

Conclusions: This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM.

Keywords: dilated cardiomyopathy; genetics; HAND1; reporter gene; transcription factor
Corresponding authors: Dr. Yi-Meng Zhou, Department of Emergency Medicine, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, P.R. China, Phone: +86 21 65690520, Fax: +86 21 65696249, E-mail: ; and Dr. Yi-Qing Yang, Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, P.R. China, Phone: +86 21 62821990, Fax: +86 21 62821105, E-mail:
aYi-Meng Zhou and Xiao-Yong Dai contributed equally to this work.

Acknowledgments

We are thankful to the study subjects for their participation in this study. This work was supported in part by grants from the National Natural Science Fund of China (81270161 and 81470372), the key program for Basic Research of Shanghai, China (14JC1405500), the Natural Science Fund of Shanghai, China (13ZR1438400, 14ZR1438000 and 15ZR1438100), the experimental animal program of Shanghai, China (14140903600 and 12140902800), and the key project of Shanghai Chest Hospital, China (2014YZDH10102 and 2014YZDH20500).

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

1. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 2013;10:531–47.10.1038/nrcardio.2013.105Suche in Google Scholar PubMed

2. Lakdawala NK, Winterfield JR, Funke BH. Dilated cardiomyopathy. Circ Arrhythm Electrophysiol 2013;6:228–37.10.1161/CIRCEP.111.962050Suche in Google Scholar PubMed PubMed Central

3. McNally EM, Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest 2013;123:19–26.10.1172/JCI62862Suche in Google Scholar PubMed PubMed Central

4. Arndt AK, Schafer S, Drenckhahn JD, Sabeh MK, Plovie ER, Caliebe A, et al. Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy. Am J Hum Genet 2013;93:67–77.10.1016/j.ajhg.2013.05.015Suche in Google Scholar PubMed PubMed Central

5. Dhandapany PS, Razzaque MA, Muthusami U, Kunnoth S, Edwards JJ, Mulero-Navarro S, et al. RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat Genet 2014;46:635–9.10.1038/ng.2963Suche in Google Scholar PubMed PubMed Central

6. Agrawal PB, Pierson CR, Joshi M, Liu X, Ravenscroft G, Moghadaszadeh B, et al. SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. Am J Hum Genet 2014;95:218–26.10.1016/j.ajhg.2014.07.004Suche in Google Scholar PubMed PubMed Central

7. Reinstein E, Orvin K, Tayeb-Fligelman E, Stiebel-Kalish H, Tzur S, Pimienta AL, et al. Mutations in TAX1BP3 cause dilated cardiomyopathy with septo-optic dysplasia. Hum Mutat 2015;36:439–42.10.1002/humu.22759Suche in Google Scholar PubMed

8. Liaquat A, Shauket U, Ahmad W, Javed Q. The tumor necrosis factor-α-238G/A and IL-6 -572G/C gene polymorphisms and the risk of idiopathic dilated cardiomyopathy: a meta-analysis of 25 studies including 9493 cases and 13,971 controls. Clin Chem Lab Med 2015;53:307–18.10.1515/cclm-2014-0502Suche in Google Scholar PubMed

9. Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 2015;36:1123–35a.10.1093/eurheartj/ehu301Suche in Google Scholar PubMed

10. Akazawa H, Komuro I. Cardiac transcription factor Csx/Nkx2-5: Its role in cardiac development and diseases. Pharmacol Ther 2005;107:252–68.10.1016/j.pharmthera.2005.03.005Suche in Google Scholar PubMed

11. Pikkarainen S, Tokola H, Kerkelä R, Ruskoaho H. GATA transcription factors in the developing and adult heart. Cardiovasc Res 2004;63:196–207.10.1016/j.cardiores.2004.03.025Suche in Google Scholar

12. Greulich F, Rudat C, Kispert A. Mechanisms of T-box gene function in the developing heart. Cardiovasc Res 2011;91:212–22.10.1093/cvr/cvr112Suche in Google Scholar

13. Srivastava D. HAND proteins: molecular mediators of cardiac development and congenital heart disease. Trends Cardiovasc Med 1999;9:11–8.10.1016/S1050-1738(98)00033-4Suche in Google Scholar

14. Oka T, Xu J, Molkentin JD. Re-employment of developmental transcription factors in adult heart disease. Semin Cell Dev Biol 2007;18:117–31.10.1016/j.semcdb.2006.11.012Suche in Google Scholar

15. Stennard FA, Costa MW, Elliott DA, Rankin S, Haast SJ, Lai D, et al. Cardiac T-box factor Tbx20 directly interacts with Nkx2-5, GATA4, and GATA5 in regulation of gene expression in the developing heart. Dev Biol 2003;262:206–24.10.1016/S0012-1606(03)00385-3Suche in Google Scholar

16. Linhares VL, Almeida NA, Menezes DC, Elliott DA, Lai D, Beyer EC, et al. Transcriptional regulation of the murine Connexin40 promoter by cardiac factors Nkx2-5, GATA4 and Tbx5. Cardiovasc Res 2004;64:402–11.10.1016/j.cardiores.2004.09.021Suche in Google Scholar PubMed PubMed Central

17. Qu XK, Qiu XB, Yuan F, Wang J, Zhao CM, Liu XY, et al. A novel NKX2.5 loss-of-function mutation associated with congenital bicuspid aortic valve. Am J Cardiol 2014;114:1891–5.10.1016/j.amjcard.2014.09.028Suche in Google Scholar PubMed

18. Zhao L, Ni SH, Liu XY, Wei D, Yuan F, Xu L, et al. Prevalence and spectrum of Nkx2.6 mutations in patients with congenital heart disease. Eur J Med Genet 2014;57:579–86.10.1016/j.ejmg.2014.08.005Suche in Google Scholar PubMed

19. Yang YQ, Gharibeh L, Li RG, Xin YF, Wang J, Liu ZM, et al. GATA4 loss-of-function mutations underlie familial tetralogy of fallot. Hum Mutat 2013;34:1662–71.10.1002/humu.22434Suche in Google Scholar PubMed

20. Shi LM, Tao JW, Qiu XB, Wang J, Yuan F, Xu L, et al. GATA5 loss-of-function mutations associated with congenital bicuspid aortic valve. Int J Mol Med 2014;33:1219–26.10.3892/ijmm.2014.1700Suche in Google Scholar PubMed

21. Huang RT, Xue S, Xu YJ, Yang YQ. Somatic mutations in the GATA6 gene underlie sporadic tetralogy of Fallot. Int J Mol Med 2013;31:51–8.10.3892/ijmm.2012.1188Suche in Google Scholar PubMed

22. Xu YJ, Chen S, Zhang J, Fang SH, Guo QQ, Wang J, et al. Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion. BMC Med Genet 2014;15:78.10.1186/1471-2350-15-78Suche in Google Scholar PubMed PubMed Central

23. Baban A, Postma AV, Marini M, Trocchio G, Santilli A, Pelegrini M, et al. Identification of TBX5 mutations in a series of 94 patients with tetralogy of Fallot. Am J Med Genet A 2014;164:3100–7.10.1002/ajmg.a.36783Suche in Google Scholar PubMed

24. Pan Y, Geng R, Zhou N, Zheng GF, Zhao H, Wang J, et al. TBX20 loss-of-function mutation contributes to double outlet right ventricle. Int J Mol Med 2015;35:1058–66.10.3892/ijmm.2015.2077Suche in Google Scholar PubMed

25. Reamon-Buettner SM, Ciribilli Y, Inga A, Borlak J. A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts. Hum Mol Genet 2008;17:1397–405.10.1093/hmg/ddn027Suche in Google Scholar PubMed

26. McCulley DJ, Black BL. Transcription factor pathways and congenital heart disease. Curr Top Dev Biol 2012;100:253–77.10.1016/B978-0-12-387786-4.00008-7Suche in Google Scholar PubMed PubMed Central

27. Costa MW, Guo G, Wolstein O, Vale M, Castro ML, Wang L, et al. Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy. Circ Cardiovasc Genet 2013;6:238–47.10.1161/CIRCGENETICS.113.000057Suche in Google Scholar PubMed PubMed Central

28. Yuan F, Qiu XB, Li RG, Qu XK, Wang J, Xu YJ, et al. A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias. Int J Mol Med 2015;35:478–86.10.3892/ijmm.2014.2029Suche in Google Scholar PubMed

29. Li RG, Li L, Qiu XB, Yuan F, Xu L, Li X, et al. GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy. Biochem Biophys Res Commun 2013;439:591–6.10.1016/j.bbrc.2013.09.023Suche in Google Scholar PubMed

30. Li J, Liu WD, Yang ZL, Yuan F, Xu L, Li RG, et al. Prevalence and spectrum of GATA4 mutations associated with sporadic dilated cardiomyopathy. Gene 2014;548:174–81.10.1016/j.gene.2014.07.022Suche in Google Scholar PubMed

31. Zhao L, Xu JH, Xu WJ, Yu H, Wang Q, Zheng HZ, et al. A novel GATA4 loss-of-function mutation responsible for familial dilated cardiomyopathy. Int J Mol Med 2014;33:654–60.10.3892/ijmm.2013.1600Suche in Google Scholar PubMed

32. Zhang XL, Dai N, Tang K, Chen YQ, Chen W, Wang J, et al. GATA5 loss-of-function mutation in familial dilated cardiomyopathy. Int J Mol Med 2015;35:763–70.10.3892/ijmm.2014.2050Suche in Google Scholar PubMed

33. Xu L, Zhao L, Yuan F, Jiang WF, Liu H, Li RG, et al. GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy. Int J Mol Med 2014;34:1315–22.10.3892/ijmm.2014.1896Suche in Google Scholar PubMed

34. Zhang XL, Qiu XB, Yuan F, Wang J, Zhao CM, Li RG, et al. TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy. Biochem Biophys Res Commun 2015;459:166–71.10.1016/j.bbrc.2015.02.094Suche in Google Scholar PubMed

35. Zhou W, Zhao L, Jiang JQ, Jiang WF, Yang YQ, Qiu XB. A novel TBX5 loss-of-function mutation associated with sporadic dilated cardiomyopathy. Int J Mol Med 2015;36:282–8.10.3892/ijmm.2015.2206Suche in Google Scholar PubMed

36. Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro ML, et al. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy. Am J Hum Genet 2007;81:280–91.10.1086/519530Suche in Google Scholar PubMed PubMed Central

37. Zhao CM, Sun B, Song HM, Wang J, Xu WJ, Jiang JF, et al. TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy. Clin Chem Lab Med 2016;54:325–32.10.1515/cclm-2015-0328Suche in Google Scholar PubMed

38. Elliott P, O’Mahony C, Syrris P, Evans A, Rivera Sorensen C, Sheppard MN, et al. Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy. Circ Cardiovasc Genet 2010;3:314–22.10.1161/CIRCGENETICS.110.937805Suche in Google Scholar PubMed

39. Wei D, Bao H, Zhou N, Zheng GF, Liu XY, Yang YQ. GATA5 loss-of-function mutation responsible for the congenital ventriculoseptal defect. Pediatr Cardiol 2013;34:504–11.10.1007/s00246-012-0482-6Suche in Google Scholar PubMed

40. Morin S, Pozzulo G, Robitaille L, Cross J, Nemer M. MEF2-dependent recruitment of the HAND1 transcription factor results in synergistic activation of target promoters. J Biol Chem 2005;16:32272–8.10.1074/jbc.M507640200Suche in Google Scholar PubMed

41. Thattaliyath BD, Livi CB, Steinhelper ME, Toney GM, Firulli AB. HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy. Biochem Biophys Res Commun 2002;297:870–75.10.1016/S0006-291X(02)02297-0Suche in Google Scholar

42. Knöfler M, Meinhardt G, Vasicek R, Husslein P, Egarter C. Molecular cloning of the human Hand1 gene/cDNA and its tissue-restricted expression in cytotrophoblastic cells and heart. Gene 1998;224:77–86.10.1016/S0378-1119(98)00511-3Suche in Google Scholar

43. McFadden DG, Barbosa AC, Richardson JA, Schneider MD, Srivastava D, Olson EN. The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner. Development 2005;132:189–201.10.1242/dev.01562Suche in Google Scholar PubMed

44. Risebro CA, Smart N, Dupays L, Breckenridge R, Mohun TJ, Riley PR. Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart. Development 2006;133:4595–606.10.1242/dev.02625Suche in Google Scholar PubMed

45. Breckenridge RA, Zuberi Z, Gomes J, Orford R, Dupays L, Felkin LE, et al. Overexpression of the transcription factor Hand1 causes predisposition towards arrhythmia in mice. J Mol Cell Cardiol 2009;47:133–41.10.1016/j.yjmcc.2009.04.007Suche in Google Scholar PubMed

46. Riley P, Anson-Cartwright L, Cross JC. The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis. Nat Genet 1998;18:271–5.10.1038/ng0398-271Suche in Google Scholar PubMed

47. Reamon-Buettner SM, Ciribilli Y, Traverso I, Kuhls B, Inga A, Borlak J. A functional genetic study identifies HAND1 mutations in septation defects of the human heart. Hum Mol Genet 2009;18:3567–78.10.1093/hmg/ddp305Suche in Google Scholar PubMed

Received: 2015-8-9
Accepted: 2015-10-13
Published Online: 2015-11-18
Published in Print: 2016-7-1

©2016 by De Gruyter

Artikel in diesem Heft

  1. Frontmatter
  2. In Memoriam: Gérard Siest (1936–2016)
  3. Editorials
  4. Improving diagnosis and reducing diagnostic errors: the next frontier of laboratory medicine
  5. The quality indicator paradox
  6. Review
  7. Clinical utility of the (-2)proPSA and evaluation of the evidence: a systematic review
  8. Mini Review
  9. Why are clinical practice guidelines not followed?
  10. EFLM Position Paper
  11. Patient identification and tube labelling – a call for harmonisation
  12. Genetics and Molecular Diagnostics
  13. A fast and simple method for detecting and quantifying donor-derived cell-free DNA in sera of solid organ transplant recipients as a biomarker for graft function
  14. Performance of two commercially available BCR-ABL1 quantification assays that use an international reporting scale
  15. HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy
  16. General Clinical Chemistry and Laboratory Medicine
  17. Performance criteria and quality indicators for the post-analytical phase
  18. Assessing the commutability of reference material formats for the harmonization of amyloid-β measurements
  19. Quantitative determination of four immunosuppressants by high resolution mass spectrometry (HRMS)
  20. Measurement of plasma vitamin K1 (phylloquinone) and K2 (menaquinones-4 and -7) using HPLC-tandem mass spectrometry
  21. Therapeutic drug monitoring of infliximab: performance evaluation of three commercial ELISA kits
  22. High level of oxysterols in neonatal cholestasis: a pitfall in analysis of biochemical markers for Niemann-Pick type C disease
  23. Reference Values and Biological Variations
  24. Reference intervals of plasma homoarginine from the German Gutenberg Health Study
  25. TSH and fT4 during pregnancy: an observational study and a review of the literature
  26. Cancer Diagnostics
  27. Mean corpuscular volume levels and all-cause and liver cancer mortality
  28. Cardiovascular Diseases
  29. Circulating endothelial-derived apoptotic microparticles and insulin resistance in non-diabetic patients with chronic heart failure
  30. Hematology and Coagulation
  31. Platelet aggregation in response to ADP is highly variable in normal donors and patients on anti-platelet medication
  32. Letters to the Editor
  33. EQA-derived metrics to assess overall instrument performance
  34. Misidentification in laboratory medicine and diagnostic process: a neglected problem calling for action
  35. Impact of the routine implementation of automated indirect immunofluorescence antinuclear antibody analysis: 1 year of experience
  36. The importance of angiogenic markers in the differential diagnosis of HELLP syndrome vs. non-HELLP thrombocytopenia
  37. Bisalbuminemia accompanying bisalbuminuria detected in capillary electrophoresis, not in gel electrophoresis
  38. Prognostic value of red blood cell distribution width in acute pancreatitis patients admitted to intensive care units: an analysis of a publicly accessible clinical database MIMIC II
  39. Differences in analytical and biological results between older and newer lots of a widely used irisin immunoassay question the validity of previous studies
  40. A diagnostic algorithm for the detection of inhibitors against coagulation Factor V
  41. Interference of anticoagulants on coagulation testing
  42. Congress Abstracts
  43. Swiss MedLab 2016 and 74th Annual Meeting of the Swiss Society of Microbiology SSM, Bern, 13–16 June 2016
https://doi.org/10.1515/cclm-2015-0766
Schlagwörter für diesen Artikel
dilated cardiomyopathy; genetics; HAND1; reporter gene; transcription factor

Artikel in diesem Heft

  1. Frontmatter
  2. In Memoriam: Gérard Siest (1936–2016)
  3. Editorials
  4. Improving diagnosis and reducing diagnostic errors: the next frontier of laboratory medicine
  5. The quality indicator paradox
  6. Review
  7. Clinical utility of the (-2)proPSA and evaluation of the evidence: a systematic review
  8. Mini Review
  9. Why are clinical practice guidelines not followed?
  10. EFLM Position Paper
  11. Patient identification and tube labelling – a call for harmonisation
  12. Genetics and Molecular Diagnostics
  13. A fast and simple method for detecting and quantifying donor-derived cell-free DNA in sera of solid organ transplant recipients as a biomarker for graft function
  14. Performance of two commercially available BCR-ABL1 quantification assays that use an international reporting scale
  15. HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy
  16. General Clinical Chemistry and Laboratory Medicine
  17. Performance criteria and quality indicators for the post-analytical phase
  18. Assessing the commutability of reference material formats for the harmonization of amyloid-β measurements
  19. Quantitative determination of four immunosuppressants by high resolution mass spectrometry (HRMS)
  20. Measurement of plasma vitamin K1 (phylloquinone) and K2 (menaquinones-4 and -7) using HPLC-tandem mass spectrometry
  21. Therapeutic drug monitoring of infliximab: performance evaluation of three commercial ELISA kits
  22. High level of oxysterols in neonatal cholestasis: a pitfall in analysis of biochemical markers for Niemann-Pick type C disease
  23. Reference Values and Biological Variations
  24. Reference intervals of plasma homoarginine from the German Gutenberg Health Study
  25. TSH and fT4 during pregnancy: an observational study and a review of the literature
  26. Cancer Diagnostics
  27. Mean corpuscular volume levels and all-cause and liver cancer mortality
  28. Cardiovascular Diseases
  29. Circulating endothelial-derived apoptotic microparticles and insulin resistance in non-diabetic patients with chronic heart failure
  30. Hematology and Coagulation
  31. Platelet aggregation in response to ADP is highly variable in normal donors and patients on anti-platelet medication
  32. Letters to the Editor
  33. EQA-derived metrics to assess overall instrument performance
  34. Misidentification in laboratory medicine and diagnostic process: a neglected problem calling for action
  35. Impact of the routine implementation of automated indirect immunofluorescence antinuclear antibody analysis: 1 year of experience
  36. The importance of angiogenic markers in the differential diagnosis of HELLP syndrome vs. non-HELLP thrombocytopenia
  37. Bisalbuminemia accompanying bisalbuminuria detected in capillary electrophoresis, not in gel electrophoresis
  38. Prognostic value of red blood cell distribution width in acute pancreatitis patients admitted to intensive care units: an analysis of a publicly accessible clinical database MIMIC II
  39. Differences in analytical and biological results between older and newer lots of a widely used irisin immunoassay question the validity of previous studies
  40. A diagnostic algorithm for the detection of inhibitors against coagulation Factor V
  41. Interference of anticoagulants on coagulation testing
  42. Congress Abstracts
  43. Swiss MedLab 2016 and 74th Annual Meeting of the Swiss Society of Microbiology SSM, Bern, 13–16 June 2016
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