Identification and Analysis of KLF13 Variants in Patients with Congenital Heart Disease

Overview

Journal BMC Med Genet

Publisher Biomed Central

Specialty Genetics

Date 2020 Apr 16

PMID 32293321

Citations 8

Authors

Wenjuan Li

Baolei Li

Tingting Li

Ergeng Zhang

Qingjie Wang

Sun Chen

Kun Sun

Affiliations

Soon will be listed here.

Abstract

Background: The protein Kruppel-like factor 13 (KLF13) is a member of the KLF family and has been identified as a cardiac transcription factor that is involved in heart development. However, the relationship between KLF13 variants and CHDs in humans remains largely unknown. The present study aimed to screen the KLF13 variants in CHD patients and genetically analyze the functions of these variants.

Methods: KLF13 variants were sequenced in a cohort of 309 CHD patients and population-matched healthy controls (n = 200) using targeted sequencing. To investigate the effect of variants on the functional properties of the KLF13 protein, the expression and subcellular localization of the protein, as well as the transcriptional activities of downstream genes and physical interactions with other transcription factors, were assessed.

Results: Two heterozygous variants, c.487C > T (P163S) and c.467G > A (S156N), were identified in two out of 309 CHD patients with tricuspid valve atresia and transposition of the great arteries, respectively. No variants were found among healthy controls. The variant c.467G > A (S156N) had increased protein expression and enhanced functionality compared with the wild type, without affecting the subcellular localization. The other variant, c.487C > T (P163S), did not show any abnormalities in protein expression or subcellular localization; however, it inhibited the transcriptional activities of downstream target genes and physically interacted with TBX5, another cardiac transcription factor.

Conclusion: Our results show that the S156N and P163S variants may affect the transcriptional function of KLF13 and physical interaction with TBX5. These results identified KLF13 as a potential genetic risk factor for congenital heart disease.

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References

Song A, Patel A, Thamatrakoln K, Liu C, Feng D, Clayberger C . Functional domains and DNA-binding sequences of RFLAT-1/KLF13, a Krüppel-like transcription factor of activated T lymphocytes. J Biol Chem. 2002; 277(33):30055-65. DOI: 10.1074/jbc.M204278200. View

Huang R, Wang J, Xue S, Qiu X, Shi H, Li R . TBX20 loss-of-function mutation responsible for familial tetralogy of Fallot or sporadic persistent truncus arteriosus. Int J Med Sci. 2017; 14(4):323-332. PMC: 5436474. DOI: 10.7150/ijms.17834. View

Derwinska K, Bartnik M, Wisniowiecka-Kowalnik B, Jagla M, Rudzinski A, Pietrzyk J . Assessment of the role of copy-number variants in 150 patients with congenital heart defects. Med Wieku Rozwoj. 2013; 16(3):175-82. View

Eisenberg L, Markwald R . Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ Res. 1995; 77(1):1-6. DOI: 10.1161/01.res.77.1.1. View

Chen C, Chen C, Chern S, Wu P, Chen S, Wu F . Detection of de novo del(18)(q22.2) and a familial of 15q13.2-q13.3 microduplication in a fetus with congenital heart defects. Taiwan J Obstet Gynecol. 2019; 58(5):704-708. DOI: 10.1016/j.tjog.2019.07.022. View

Lomberk G, Urrutia R . The family feud: turning off Sp1 by Sp1-like KLF proteins. Biochem J. 2005; 392(Pt 1):1-11. PMC: 1317658. DOI: 10.1042/BJ20051234. View

Zhao Q, Ma X, Jia B, Huang G . Prevalence of congenital heart disease at live birth: an accurate assessment by echocardiographic screening. Acta Paediatr. 2013; 102(4):397-402. DOI: 10.1111/apa.12170. View

Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S . Krüppel-like transcription factors: a functional family. Int J Biochem Cell Biol. 2007; 40(10):1996-2001. DOI: 10.1016/j.biocel.2007.07.018. View

Anderson R, Webb S, Brown N, Lamers W, Moorman A . Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks. Heart. 2003; 89(9):1110-8. PMC: 1767864. DOI: 10.1136/heart.89.9.1110. View

10.

Martin K, Metcalfe J, Kemp P . Expression of Klf9 and Klf13 in mouse development. Mech Dev. 2001; 103(1-2):149-51. DOI: 10.1016/s0925-4773(01)00343-4. View

11.

van Bon B, Mefford H, Menten B, Koolen D, Sharp A, Nillesen W . Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet. 2009; 46(8):511-23. PMC: 3395372. DOI: 10.1136/jmg.2008.063412. View

12.

Nemer M, Horb M . The KLF family of transcriptional regulators in cardiomyocyte proliferation and differentiation. Cell Cycle. 2007; 6(2):117-21. DOI: 10.4161/cc.6.2.3718. View

13.

Temsah R, Nemer M . GATA factors and transcriptional regulation of cardiac natriuretic peptide genes. Regul Pept. 2005; 128(3):177-85. DOI: 10.1016/j.regpep.2004.12.026. View

14.

CAMERON J, Rosenthal A, Olson A . Malnutrition in hospitalized children with congenital heart disease. Arch Pediatr Adolesc Med. 1995; 149(10):1098-102. DOI: 10.1001/archpedi.1995.02170230052007. View

15.

Yang Y, Gharibeh L, Li R, Xin Y, Wang J, Liu Z . GATA4 loss-of-function mutations underlie familial tetralogy of fallot. Hum Mutat. 2013; 34(12):1662-71. DOI: 10.1002/humu.22434. View

16.

Garg V, Kathiriya I, Barnes R, Schluterman M, King I, Butler C . GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature. 2003; 424(6947):443-7. DOI: 10.1038/nature01827. View

17.

Hariri F, Nemer M, Nemer G . T-box factors: insights into the evolutionary emergence of the complex heart. Ann Med. 2011; 44(7):680-93. DOI: 10.3109/07853890.2011.607468. View

18.

Hayek S, Nemer M . Cardiac natriuretic peptides: from basic discovery to clinical practice. Cardiovasc Ther. 2010; 29(6):362-76. DOI: 10.1111/j.1755-5922.2010.00152.x. View

19.

Lavallee G, Andelfinger G, Nadeau M, Lefebvre C, Nemer G, Horb M . The Kruppel-like transcription factor KLF13 is a novel regulator of heart development. EMBO J. 2006; 25(21):5201-13. PMC: 1630408. DOI: 10.1038/sj.emboj.7601379. View

20.

Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R . Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat Genet. 2001; 28(3):276-80. DOI: 10.1038/90123. View