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Cited by 24Congenital heart defects researchCardiac electrophysiology and arrhythmiasCongenital Heart Disease Studies

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Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

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Qian, Yanyan, Xiao, Deyong, Guo, Xiao, Chen, Hongbo, Hao, Lili, Ma, Xiaojing, Huang, Guoying, Ma, Duan, Wang, Huijun·2017·Journal of Translational Medicine
DOI 10.1186/s12967-017-1173-0PMC PMC5379520
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Abstract

BACKGROUND: Congenital heart disease (CHD) is a common birth defect, and most cases occur sporadically. Mutations in key genes that are responsible for cardiac development could contribute to CHD. To date, the genetic causes of CHD remain largely unknown. METHODS: In this study, twenty-nine candidate genes in CHD were sequenced in 106 patients with Tetralogy of Fallot (TOF) using target exome sequencing (TES). The co-immunoprecipitation (CO-IP) and luciferase reporter gene assays were performed in HEK293T cells, and wild-type and mutant mRNA of ZFPM2 were microinjected into zebrafish embryos. RESULTS: Rare variants in key cardiac transcriptional factors and JAG1 were identified in the patients. Four patients carried multiple gene variants. The novel E1148K variant was located at the eighth Zinc-finger domain of FOG2 protein. The CO-IP assays in the HEK293T cells revealed that the variant significantly damaged the interaction between ZFPM2/FOG2 and GATA4. The luciferase reporter gene assays revealed that the E1148K mutant ZFPM2 protein displayed a significantly greater inhibition of the transcriptional activation of GATA4 than the wild-type protein. The wild-type mRNA and the E1148K mutant mRNA of ZFPM2 were injected into zebrafish embryos. At 48 hpf, in the mutant mRNA injection group, the number of embryos with an abnormal cardiac chamber structure and a loss of left-right asymmetry was increased. By 72 hpf, the defects in the chamber and left-right asymmetry became obvious. CONCLUSIONS: We performed TES in sporadic TOF patients and identified rare variants in candidate genes in CHD. We first validated the E1148 K variant in ZFPM2, which is likely involved in the pathogenesis of CHD via GATA4. Moreover, our results suggest that TES could be a useful tool for discovering sequence variants in CHD patients.

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Fig. 1 Variants in the GATA family members. Blue boxes represent the transcription activation domains (TADs), and red boxes indicate the Zinc finger domains (ZFN). Sanger sequencing data are displayed, and the variants are shown in the red frames. Alignment of amino acid residues adjacent to the variants shows a conservation among different species, including human, mouse, dog and zebrafish. a Human GATA4 protein domain with the variants identified in the TOF patients. The GATA4 protein is composed of four functional domains. V380 M is located in the second TAD, and P407Q is located near the second TAD. Sanger sequencing data are displayed, and the variants are shown in the red frames. Amino acid in 407 is conserved in human, mouse and dog but not in zebrafish. b Human GATA5 protein domain with the variants identified in the TOF patients. GATA5 protein also has four functional domains, and the two novel variants are not located in the functional domain. Sanger sequencing data are displayed, and the variants are shown in the red frames. c Human GATA6 protein domain with the variants identified in the TOF patients. The GATA6 protein has five functional domains, including two TADs, two ZNFs and one nuclear location signal (NLS), which is presented by the yellow box. The variants D111 N and H324Q are localized at the TAD1 and TAD2, respectively. The amino acid in 111 is highly conserved in human, mouse, dog and zebrafish
Fig. 1 Variants in the GATA family members. Blue boxes represent the transcription activation domains (TADs), and red boxes indicate the Zinc finger domains (ZFN). Sanger sequencing data are displayed, and the variants are shown in the red frames. Alignment of amino acid residues adjacent to the variants shows a conservation among different species, including human, mouse, dog and zebrafish. a Human GATA4 protein domain with the variants identified in the TOF patients. The GATA4 protein is composed of four functional domains. V380 M is located in the second TAD, and P407Q is located near the second TAD. Sanger sequencing data are displayed, and the variants are shown in the red frames. Amino acid in 407 is conserved in human, mouse and dog but not in zebrafish. b Human GATA5 protein domain with the variants identified in the TOF patients. GATA5 protein also has four functional domains, and the two novel variants are not located in the functional domain. Sanger sequencing data are displayed, and the variants are shown in the red frames. c Human GATA6 protein domain with the variants identified in the TOF patients. The GATA6 protein has five functional domains, including two TADs, two ZNFs and one nuclear location signal (NLS), which is presented by the yellow box. The variants D111 N and H324Q are localized at the TAD1 and TAD2, respectively. The amino acid in 111 is highly conserved in human, mouse, dog and zebrafishCC BY · PubMed Central
Fig. 2 The variant of ZFPM2 attenuated the transcriptional activation of GATA4 and contributed to the cardiac abnormalities in zebrafish. a Diagram of the human ZFPM2/FOG2 protein domain with the location of its variants identified. The eight zinc-finger motifs (ZNF) are represented by yellow boxes. The nuclear localization signal (NLS) is indicated by a green box. The putative CtBP-binding site (CBS) is represented by a pink box. The N-terminal transcriptional repression domain (TRD) is indicated by a blue box. E1148 K found in B430 is located at the eighth Zinc-finger domain, and E1005G found in B548 is located in the seventh and eighth domains. Sanger sequencing shows the variant in the red frame. Both are conserved in human, mouse, dog and zebrafish. The amino acid residue altered by the mutation is shown in the red box. b Co-immunoprecipitation assays in HEK293T cells revealed that the E1148 K variant significantly damaged the interaction between ZFPM2 and GATA4 on the western blot. The semi-quantitative analysis of the western blot results shows that the E1148 K mutant ZFPM2 protein significantly disrupted the interaction with GATA4 compared to the wild-type ZFPM2 protein. The experiment was repeated three times. (p < 0.05 *, p < 0.01 **) c Luciferase reported gene assays were performed. The result revealed that the wild-type ZFPM2 protein could inhibit the transcriptional activation of GATA4 on the promoter of ANF. Furthermore, E1148 K inhibited the transcriptional activation of the GATA4 on the ANF promoter significantly more than the WT. Experiments were performed in triplicate, and the mean and standard deviations are shown. (*p < 0.05 and **p < 0.01). d Overexpression of the mutant ZFPM2 protein (E1148 K) contributes to the abnormal cardiac morphogenesis in the zebrafish embryos. In the control and wild-type human ZFPM2 mRNA injection groups, the embryos show normal cardiac left–right asymmetry at 48 and 72 hpf. The normal cardiac left–right asymmetry is “left (L)”: the ventricle is on the left side of the midline, and the atrium is on the right side. However, in the mutant mRNA injection group, the embryos showed the “right (R)” or “straight (S)” abnormal left–right asymmetry. e In each group, the cardiac morphogenesis of fifty embryos (n = 50) was analyzed. The number of embryos with cardiac defects, including size, left–right asymmetry, looping and pericardialites, was counted. The proportion of embryos with cardiac defects in the mutant human ZFPM2 protein (E1148 K) injection group is significantly higher than that in the other two groups. Three independent experiments were performed. (*p < 0.05 and **p < 0.01). f The nppa (zebrafish ANF gene) mRNA level in the embryos that received the E1148 K mutant human ZFPM2 mRNA injection is lower than that in the wild-type human ZFPM2 mRNA injection group. The mean and standard deviations are shown. Experiments were performed in triplicate. (*p < 0.05 and **p < 0.01)
Fig. 2 The variant of ZFPM2 attenuated the transcriptional activation of GATA4 and contributed to the cardiac abnormalities in zebrafish. a Diagram of the human ZFPM2/FOG2 protein domain with the location of its variants identified. The eight zinc-finger motifs (ZNF) are represented by yellow boxes. The nuclear localization signal (NLS) is indicated by a green box. The putative CtBP-binding site (CBS) is represented by a pink box. The N-terminal transcriptional repression domain (TRD) is indicated by a blue box. E1148 K found in B430 is located at the eighth Zinc-finger domain, and E1005G found in B548 is located in the seventh and eighth domains. Sanger sequencing shows the variant in the red frame. Both are conserved in human, mouse, dog and zebrafish. The amino acid residue altered by the mutation is shown in the red box. b Co-immunoprecipitation assays in HEK293T cells revealed that the E1148 K variant significantly damaged the interaction between ZFPM2 and GATA4 on the western blot. The semi-quantitative analysis of the western blot results shows that the E1148 K mutant ZFPM2 protein significantly disrupted the interaction with GATA4 compared to the wild-type ZFPM2 protein. The experiment was repeated three times. (p < 0.05 *, p < 0.01 **) c Luciferase reported gene assays were performed. The result revealed that the wild-type ZFPM2 protein could inhibit the transcriptional activation of GATA4 on the promoter of ANF. Furthermore, E1148 K inhibited the transcriptional activation of the GATA4 on the ANF promoter significantly more than the WT. Experiments were performed in triplicate, and the mean and standard deviations are shown. (*p < 0.05 and **p < 0.01). d Overexpression of the mutant ZFPM2 protein (E1148 K) contributes to the abnormal cardiac morphogenesis in the zebrafish embryos. In the control and wild-type human ZFPM2 mRNA injection groups, the embryos show normal cardiac left–right asymmetry at 48 and 72 hpf. The normal cardiac left–right asymmetry is “left (L)”: the ventricle is on the left side of the midline, and the atrium is on the right side. However, in the mutant mRNA injection group, the embryos showed the “right (R)” or “straight (S)” abnormal left–right asymmetry. e In each group, the cardiac morphogenesis of fifty embryos (n = 50) was analyzed. The number of embryos with cardiac defects, including size, left–right asymmetry, looping and pericardialites, was counted. The proportion of embryos with cardiac defects in the mutant human ZFPM2 protein (E1148 K) injection group is significantly higher than that in the other two groups. Three independent experiments were performed. (*p < 0.05 and **p < 0.01). f The nppa (zebrafish ANF gene) mRNA level in the embryos that received the E1148 K mutant human ZFPM2 mRNA injection is lower than that in the wild-type human ZFPM2 mRNA injection group. The mean and standard deviations are shown. Experiments were performed in triplicate. (*p < 0.05 and **p < 0.01)CC BY · PubMed Central
Fig. 3 Rare variants of JAG1 identified in patients. Human JAG1 protein structures with the location of the variants identified are shown above the diagram. The amino acid positions of the putative JAG1 functional domains are shown below the protein diagram. Blue box represents the signal peptide, and the green box indicates the DSL domain. In addition, the dark blue boxes show the EGF repeat domains, and the orange box represents the transmembrane domain. Four variants (p.P269R, p.N504S, p. M969T, p. H1013L) of JAG1 were identified and were conservative in different species, including human, mouse, dog and zebrafish. The amino acid residue altered by the mutation is shown in the red frame. All variants were confirmed by Sanger sequencing and are shown in the red frames. The variant p. N504S is located on the EGF repeats domain, and the other three variants are not in the functional domain
Fig. 3 Rare variants of JAG1 identified in patients. Human JAG1 protein structures with the location of the variants identified are shown above the diagram. The amino acid positions of the putative JAG1 functional domains are shown below the protein diagram. Blue box represents the signal peptide, and the green box indicates the DSL domain. In addition, the dark blue boxes show the EGF repeat domains, and the orange box represents the transmembrane domain. Four variants (p.P269R, p.N504S, p. M969T, p. H1013L) of JAG1 were identified and were conservative in different species, including human, mouse, dog and zebrafish. The amino acid residue altered by the mutation is shown in the red frame. All variants were confirmed by Sanger sequencing and are shown in the red frames. The variant p. N504S is located on the EGF repeats domain, and the other three variants are not in the functional domainCC BY · PubMed Central
Fig. 4 Two possible genetic etiologies of CHD. a Monogenic mutations in a key cardiac regulator may be the cause of CHD. A pathogenic E1148 K variant of ZFPM2 in patient B430 decreased the binding of ZFPM2 and GATA4 and attenuated the transcriptional activation of GATA4 on the promoter of ANF. b The majority of the variants in the GATA family member genes and JAG1 occurred sporadically in the patients. However, patients B294 and B393 carried two variants in two genes. B393 carried one variant in JAG1 and one variant in GATA6 variant, shown in a blue color, and B294 carried one variant in JAG1 and one variant in GATA5, shown in a green color. The results support the notion that rare, moderate-effect gene variants occur simultaneously in patients and may increase the susceptibility to cardiac malformations. The interaction between NOTCH signaling and the GATA family members is indispensable for cardiac development
Fig. 4 Two possible genetic etiologies of CHD. a Monogenic mutations in a key cardiac regulator may be the cause of CHD. A pathogenic E1148 K variant of ZFPM2 in patient B430 decreased the binding of ZFPM2 and GATA4 and attenuated the transcriptional activation of GATA4 on the promoter of ANF. b The majority of the variants in the GATA family member genes and JAG1 occurred sporadically in the patients. However, patients B294 and B393 carried two variants in two genes. B393 carried one variant in JAG1 and one variant in GATA6 variant, shown in a blue color, and B294 carried one variant in JAG1 and one variant in GATA5, shown in a green color. The results support the notion that rare, moderate-effect gene variants occur simultaneously in patients and may increase the susceptibility to cardiac malformations. The interaction between NOTCH signaling and the GATA family members is indispensable for cardiac developmentCC BY · PubMed Central

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Metadata

Authors
Qian, Y., Xiao, D., Guo, X., Chen, H., Hao, L., Ma, X., Huang, G., Ma, D., & Wang, H.
Affiliations
  • Shanghai Medical College of Fudan University (CN)
  • Fudan University (CN)
  • Children's Hospital of Fudan University (CN)
Corresponding author
  • Ma, Duan
  • Wang, Huijun
ORCID
Venue
Journal of Translational Medicine
Publisher
Springer Science and Business Media LLC
Published
2017-04-03
Volume
15
Issue
1
Pages
69-69
ISSN
1479-5876 (ISSN-L)
DOI
10.1186/s12967-017-1173-0
PMC
PMC5379520
OpenAlex
W2604158690
Cited by
24
References
1
Citations by year
2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 5 · 2019: 4 · 2018: 5
FWCI
1.56
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Translational Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81471483, 81570286)
  • National Key Research and Development Program (2016YFC1000500)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Congenital Heart Disease Studies
Keywords
congenital heart disease, tetralogy of Fallot, ZFPM2, FOG2, GATA4, GATA transcription factors, JAG1, rare variants, zinc finger, transcriptional regulation, heart development, left-right asymmetry
MeSH terms
Adolescent, Amino Acid Sequence, Animals, Base Sequence, Child, Child, Preschool, Female, Gene Expression Regulation, Heart Defects, Congenital, Humans, Infant, Infant, Newborn, Male, Tetralogy of Fallot, Transcription, Genetic, Genetic Variation, Zebrafish, Transcriptional Activation, GATA Transcription Factors, HEK293 Cells

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Qian, Y., Xiao, D., Guo, X., Chen, H., Hao, L., Ma, X., Huang, G., Ma, D., & Wang, H. (2017). Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation. Journal of Translational Medicine. https://doi.org/10.1186/s12967-017-1173-0