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Predisposition to atrioventricular septal defects may be caused by SOX7 variants that impair interaction with GATA4

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Abstract

Atrioventricular septal defects (AVSD) are a complicated subtype of congenital heart defects for which the genetic basis is poorly understood. Many studies have demonstrated that the transcription factor SOX7 plays a pivotal role in cardiovascular development. However, whether SOX7 single nucleotide variants are involved in AVSD pathogenesis is unclear. To explore the potential pathogenic role of SOX7 variants, we recruited a total of 100 sporadic non-syndromic AVSD Chinese Han patients and screened SOX7 variants in the patient cohort by targeted sequencing. Functional assays were performed to evaluate pathogenicity of nonsynonymous variants of SOX7. We identified three rare SOX7 variants, c.40C > G, c.542G > A, and c.743C > T, in the patient cohort, all of which were found to be highly conserved in mammals. Compared to the wild type, these SOX7 variants had increased mRNA expression and decreased protein expression. In developing hearts, SOX7 and GATA4 were highly expressed in the region of atrioventricular cushions. Moreover, SOX7 overexpression promoted the expression of GATA4 in human umbilical vein endothelial cells. A chromatin immunoprecipitation assay revealed that SOX7 could directly bind to the GATA4 promoter and luciferase assays demonstrated that SOX7 activated the GATA4 promoter. The SOX7 variants had impaired transcriptional activity relative to wild-type SOX7. Furthermore, the SOX7 variants altered the ability of GATA4 to regulate its target genes. In conclusion, our findings showed that deleterious SOX7 variants potentially contribute to human AVSD by impairing its interaction with GATA4. This study provides novel insights into the etiology of AVSD and contributes new strategies to the prenatal diagnosis of AVSD.

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Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

AVSD:

Atrioventricular septal defect

CAVC:

Complete atrioventricular canal

ASD:

Atrial septal defect

PH:

Pulmonary hypertension

References

  • Afouda BA, Lynch AT, de Paiva AE, Hoppler S (2018) Genome-wide transcriptomics analysis identifies sox7 and sox18 as specifically regulated by gata4 in cardiomyogenesis. Dev Biol 434:108–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agopian AJ, Moulik M, Gupta-Malhotra M, Marengo LK, Mitchell LE (2012) Descriptive epidemiology of non-syndromic complete atrioventricular canal defects. Paediatr Perinat Epidemiol 26:515–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al Turki S, Manickaraj AK, Mercer CL, Gerety SS, Hitz MP, Lindsay S, D’Alessandro LC, Swaminathan GJ, Bentham J, Arndt AK, Louw J, Low J, Breckpot J, Gewillig M, Thienpont B, Abdul-Khaliq H, Harnack C, Hoff K, Kramer HH, Schubert S, Siebert R, Toka O, Cosgrove C, Watkins H, Lucassen AM, O’Kelly IM, Salmon AP, Bu’lock FA, Granados-Riveron J, Setchfield K, Thornborough C, Brook JD, Mulder B, Klaassen S, Bhattacharya S, Devriendt K, Fitzpatrick DF, Wilson DI, Mital S, Hurles ME (2014) Rare variants in NR2F2 cause congenital heart defects in humans. Am J Hum Genet 94:574–585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ang YS, Rivas RN, Ribeiro AJS, Srivas R, Rivera J, Stone NR, Pratt K, Mohamed TMA, Fu JD, Spencer CI, Tippens ND, Li M, Narasimha A, Radzinsky E, Moon-Grady AJ, Yu H, Pruitt BL, Snyder MP, Srivastava D (2016) Disease model of GATA4 mutation reveals transcription factor cooperativity in human cardiogenesis. Cell 167:1734-1749.e1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barber JC, Rosenfeld JA, Foulds N, Laird S, Bateman MS, Thomas NS, Baker S, Maloney VK, Anilkumar A, Smith WE, Banks V, Ellingwood S, Kharbutli Y, Mehta L, Eddleman KA, Marble M, Zambrano R, Crolla JA, Lamb AN (2013) 8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients. Am J Med Genet A 161:487–500

    Article  CAS  Google Scholar 

  • Barber JC, Rosenfeld JA, Graham JM, Kramer N, Lachlan KL, Bateman MS, Collinson MN, Stadheim BF, Turner CL, Gauthier JN, Reimschisel TE, Qureshi AM, Dabir TA, Humphreys MW, Marble M, Huang T, Beal SJ, Massiah J, Taylor EJ, Wynn SL (2015) Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance. Am J Med Genet A 167:2052–2064

    Article  CAS  Google Scholar 

  • Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, Bruzzone R, Quadrelli R, Lerone M, Romeo G, Silengo M, Pereira A, Krieger J, Mesquita SF, Kamisago M, Morton CC, Pierpont ME, Muller CW, Seidman JG, Seidman CE (1999) Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations. Proc Natl Acad Sci USA 96:2919–2924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Behrens AN, Zierold C, Shi X, Ren Y, Koyano-Nakagawa N, Garry DJ, Martin CM (2014) Sox7 is regulated by ETV2 during cardiovascular development. Stem Cells Dev 23:2004–2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Briggs LE, Kakarla J, Wessels A (2012) The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion. Differentiation 84:117–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Broderick TL, Parrott CR, Wang D, Jankowski M, Gutkowska J (2012) Expression of cardiac GATA4 and downstream genes after exercise training in the db/db mouse. Pathophysiology 19:193–203

    Article  CAS  PubMed  Google Scholar 

  • Bruneau BG (2013) Signaling and transcriptional networks in heart development and regeneration. Cold Spring Harb Perspect Biol 5:a008292

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Calabro R, Limongelli G (2006) Complete atrioventricular canal. Orphanet J Rare Dis 1:8

    Article  PubMed  PubMed Central  Google Scholar 

  • Calkoen EE, Hazekamp MG, Blom NA, Elders BB, Gittenberger-de Groot AC, Haak MC, Bartelings MM, Roest AA, Jongbloed MR (2016) Atrioventricular septal defect: from embryonic development to long-term follow-up. Int J Cardiol 202:784–795

    Article  PubMed  Google Scholar 

  • Cermenati S, Moleri S, Cimbro S, Corti P, Del Giacco L, Amodeo R, Dejana E, Koopman P, Cotelli F, Beltrame M (2008) Sox18 and Sox7 play redundant roles in vascular development. Blood 111:2657–2666

    Article  CAS  PubMed  Google Scholar 

  • Chiang IK, Fritzsche M, Pichol-Thievend C, Neal A, Holmes K, Lagendijk A, Overman J, D’Angelo D, Omini A, Hermkens D, Lesieur E, Liu K, Ratnayaka I, Corada M, Bou-Gharios G, Carroll J, Dejana E, Schulte-Merker S, Hogan B, Beltrame M, De Val S, Francois M (2017) SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development. Development 144:2629–2639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christensen N, Andersen H, Garne E, Wellesley D, Addor MC, Haeusler M, Khoshnood B, Mullaney C, Rankin J, Tucker D (2013) Atrioventricular septal defects among infants in Europe: a population-based study of prevalence, associated anomalies, and survival. Cardiol Young 23:560–567

    Article  PubMed  Google Scholar 

  • Costa G, Mazan A, Gandillet A, Pearson S, Lacaud G, Kouskoff V (2012) SOX7 regulates the expression of VE-cadherin in the haemogenic endothelium at the onset of haematopoietic development. Development 139:1587–1598

    Article  CAS  PubMed  Google Scholar 

  • Costa MW, Guo G, Wolstein O, Vale M, Castro ML, Wang L, Otway R, Riek P, Cochrane N, Furtado M, Semsarian C, Weintraub RG, Yeoh T, Hayward C, Keogh A, Macdonald P, Feneley M, Graham RM, Seidman JG, Seidman CE, Rosenthal N, Fatkin D, Harvey RP (2013) Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy. Circ Cardiovasc Genet 6:238–247

    Article  CAS  PubMed  Google Scholar 

  • Croquelois A, Domenighetti AA, Nemir M, Lepore M, Rosenblatt-Velin N, Radtke F, Pedrazzini T (2008) Control of the adaptive response of the heart to stress via the Notch1 receptor pathway. J Exp Med 205:3173–3185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • D’Alessandro LC, Al Turki S, Manickaraj AK, Manase D, Mulder BJ, Bergin L, Rosenberg HC, Mondal T, Gordon E, Lougheed J, Smythe J, Devriendt K, Bhattacharya S, Watkins H, Bentham J, Bowdin S, Hurles ME, Mital S (2016) Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect. Genet Med 18:189–198

    Article  CAS  PubMed  Google Scholar 

  • Doyle MJ, Magli A, Estharabadi N, Amundsen D, Mills LJ, Martin CM (2019) Sox7 regulates lineage decisions in cardiovascular progenitor cells. Stem Cells Dev 28:1089–1103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fawcett SR, Klymkowsky MW (2004) Embryonic expression of Xenopus laevis SOX7. Gene Expr Patterns 4:29–33

    Article  CAS  PubMed  Google Scholar 

  • Futaki S, Hayashi Y, Emoto T, Weber CN, Sekiguchi K (2004) Sox7 plays crucial roles in parietal endoderm differentiation in F9 embryonal carcinoma cells through regulating Gata-4 and Gata-6 expression. Mol Cell Biol 24:10492–10503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gandillet A, Serrano AG, Pearson S, Lie ALM, Lacaud G, Kouskoff V (2009) Sox7-sustained expression alters the balance between proliferation and differentiation of hematopoietic progenitors at the onset of blood specification. Blood 114:4813–4822

    Article  CAS  PubMed  Google Scholar 

  • Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447

    Article  CAS  PubMed  Google Scholar 

  • Gittenberger-de Groot AC, Calkoen EE, Poelmann RE, Bartelings MM, Jongbloed MR (2014) Morphogenesis and molecular considerations on congenital cardiac septal defects. Ann Med 46:640–652

    Article  CAS  PubMed  Google Scholar 

  • He Q, Mendez M, LaPointe MC (2002) Regulation of the human brain natriuretic peptide gene by GATA-4. Am J Physiol Endocrinol Metab 283:E50-57

    Article  CAS  PubMed  Google Scholar 

  • Herpers R, van de Kamp E, Duckers HJ, Schulte-Merker S (2008) Redundant roles for sox7 and sox18 in arteriovenous specification in zebrafish. Circ Res 102:12–15

    Article  CAS  PubMed  Google Scholar 

  • Hoffman JI, Kaplan S, Liberthson RR (2004) Prevalence of congenital heart disease. Am Heart J 147:425–439

    Article  PubMed  Google Scholar 

  • Hove JR, Koster RW, Forouhar AS, Acevedo-Bolton G, Fraser SE, Gharib M (2003) Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421:172–177

    Article  CAS  PubMed  Google Scholar 

  • Lilly AJ, Lacaud G, Kouskoff V (2017a) SOXF transcription factors in cardiovascular development. Semin Cell Dev Biol 63:50–57

    Article  CAS  PubMed  Google Scholar 

  • Lilly AJ, Mazan A, Scott DA, Lacaud G, Kouskoff V (2017b) SOX7 expression is critically required in FLK1-expressing cells for vasculogenesis and angiogenesis during mouse embryonic development. Mech Dev 146:31–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Magovern JH, Moore GW, Hutchins GM (1986) Development of the atrioventricular valve region in the human embryo. Anat Rec 215:167–181

    Article  CAS  PubMed  Google Scholar 

  • Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L (2007) Congenital heart disease in the general population: changing prevalence and age distribution. Circulation 115:163–172

    Article  PubMed  Google Scholar 

  • Murakami A, Shen H, Ishida S, Dickson C (2004) SOX7 and GATA-4 are competitive activators of Fgf-3 transcription. J Biol Chem 279:28564–28573

    Article  CAS  PubMed  Google Scholar 

  • Nelson TJ, Chiriac A, Faustino RS, Crespo-Diaz RJ, Behfar A, Terzic A (2009) Lineage specification of Flk-1+ progenitors is associated with divergent Sox7 expression in cardiopoiesis. Differentiation 77:248–255

    Article  CAS  PubMed  Google Scholar 

  • Rajagopal SK, Ma Q, Obler D, Shen J, Manichaikul A, Tomita-Mitchell A, Boardman K, Briggs C, Garg V, Srivastava D, Goldmuntz E, Broman KW, Benson DW, Smoot LB, Pu WT (2007) Spectrum of heart disease associated with murine and human GATA4 mutation. J Mol Cell Cardiol 43:677–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rani L, Mathur N, Gupta R, Gogia A, Kaur G, Dhanjal JK, Sundar D, Kumar L, Sharma A (2017) Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia. Clin Epigenet 9:57

    Article  CAS  Google Scholar 

  • 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 (2015) 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. Genet Med 17:405–424

    Article  PubMed  PubMed Central  Google Scholar 

  • Sakamoto Y, Hara K, Kanai-Azuma M, Matsui T, Miura Y, Tsunekawa N, Kurohmaru M, Saijoh Y, Koopman P, Kanai Y (2007) Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos. Biochem Biophys Res Commun 360:539–544

    Article  CAS  PubMed  Google Scholar 

  • Schrader EK, Harstad KG, Matouschek A (2009) Targeting proteins for degradation. Nat Chem Biol 5:815–822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spector LG, Menk JS, Knight JH, McCracken C, Thomas AS, Vinocur JM, Oster ME, St Louis JD, Moller JH, Kochilas L (2018) Trends in long-term mortality after congenital heart surgery. J Am Coll Cardiol 71:2434–2446

    Article  PubMed  PubMed Central  Google Scholar 

  • Srivastava D (2006) Making or breaking the heart: from lineage determination to morphogenesis. Cell 126:1037–1048

    Article  CAS  PubMed  Google Scholar 

  • Stefanovic S, Barnett P, van Duijvenboden K, Weber D, Gessler M, Christoffels VM (2014) GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development. Nat Commun 5:3680

    Article  PubMed  Google Scholar 

  • Stoll C, Dott B, Alembik Y, Roth MP (2015) Associated congenital anomalies among cases with Down syndrome. Eur J Med Genet 58:674–680

    Article  PubMed  Google Scholar 

  • Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, Mering CV (2019) STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47:D607-d613

    Article  CAS  PubMed  Google Scholar 

  • Takash W, Canizares J, Bonneaud N, Poulat F, Mattei MG, Jay P, Berta P (2001) SOX7 transcription factor: sequence, chromosomal localisation, expression, transactivation and interference with Wnt signalling. Nucleic Acids Res 29:4274–4283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW (2011) Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 58:2241–2247

    Article  PubMed  Google Scholar 

  • Wat JJ, Wat MJ (2014) Sox7 in vascular development: review, insights and potential mechanisms. Int J Dev Biol 58:1–8

    Article  CAS  PubMed  Google Scholar 

  • Wat MJ, Beck TF, Hernandez-Garcia A, Yu Z, Veenma D, Garcia M, Holder AM, Wat JJ, Chen Y, Mohila CA, Lally KP, Dickinson M, Tibboel D, de Klein A, Lee B, Scott DA (2012) Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1. Hum Mol Genet 21:4115–4125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Webb S, Brown NA, Anderson RH (1998) Formation of the atrioventricular septal structures in the normal mouse. Circ Res 82:645–656

    Article  CAS  PubMed  Google Scholar 

  • Webb S, Anderson RH, Lamers WH, Brown NA (1999) Mechanisms of deficient cardiac septation in the mouse with trisomy 16. Circ Res 84:897–905

    Article  CAS  PubMed  Google Scholar 

  • Xin M, Olson EN, Bassel-Duby R (2013) Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat Rev Mol Cell Biol 14:529–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin Y, Morgunova E, Jolma A, Kaasinen E, Sahu B, Khund-Sayeed S, Das PK, Kivioja T, Dave K, Zhong F, Nitta KR, Taipale M, Popov A, Ginno PA, Domcke S, Yan J, Schubeler D, Vinson C, Taipale J (2017) Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. https://doi.org/10.1126/science.aaj2239

    Article  PubMed  PubMed Central  Google Scholar 

  • Zaidi S, Brueckner M (2017) Genetics and genomics of congenital heart disease. Circ Res 120:923–940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W, Xu W, Chen W, Zhou Q (2018) Interplay of autophagy inducer rapamycin and proteasome inhibitor MG132 in reduction of foam cell formation and inflammatory cytokine expression. Cell Transplant 27:1235–1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou L, Liu J, Xiang M, Olson P, Guzzetta A, Zhang K, Moskowitz IP, Xie L (2017) Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation. Proc Natl Acad Sci USA 114:e1422–e1431

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors appreciate all subjects participated in the study and all the members from the Lab of Pediatric Cardiovascular at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. This manuscript has been released as a pre-print at Research Square, Baolei Li, Zhuoyan Li, Jianping Yang et al. Three rare variants of SOX7 impairing its interaction with GATA4 may be a predisposing factor to complete AVSD, 28 May 2020, PREPRINT (Version 1). https://dx.doi.org/10.21203/rs.3.rs-30638/v1.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82071936, 81741066, 81670285, 81974021, 81974012 and 82170232), National Key R&D Program of China (No. 2018YFC1002400), Translational Medicine Cross-Research Fund of Shanghai Jiao Tong University (No. ZH2018ZDA10), Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (No. 17YJJ28) and the Clinical Research Capability Enhancement Program for the Master of Pediatrics of Shanghai Jiao Tong University School of Medicine (No. EKKY2018001DGD).

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  1. Baolei Li and Zhuoyan Li contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, No.1665 Kongjiang Road, Shanghai, 200092, China

    Baolei Li, Zhuoyan Li, Jianping Yang, Nanchao Hong, Lihui Jin, Yuejuan Xu, Kun Sun, Yu Yu, Yanan Lu & Sun Chen

  2. Medical Laboratory, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Qihua Fu

  3. Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China

    Yu Yu

  4. Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China

    Yanan Lu

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  1. Baolei Li
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Contributions

SC and YL conceived and designed the study. BL, ZL, and NH performed the experiments; JY, LJ, YY, and KS analyzed the data; YX, QF, and JY collected the blood samples from all subjects. BL drafted the manuscript. SC and YL revised the manuscript. All authors contributed to writing this paper and approved the final manuscript.

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Correspondence to Yanan Lu or Sun Chen.

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The authors state that they have no conflicts of interest.

Ethics approval

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Medical Ethics Committee of Shanghai Xinhua Hospital (Approval No. XHEC-C-2017–265) and Shanghai Children’s Medical Center (Approval No. SCMC-201015).

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Written informed consent was obtained from parents or legal guardians before inclusion for all children enrolled into this study.

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Communicated by Shuhua Xu.

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Supplementary Information

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438_2022_1859_MOESM1_ESM.tif

Supplementary file1 Supplemental Figure 1. Complementary sequence chromatograms of SOX7 missense variants in patients. (TIF 21995 KB)

438_2022_1859_MOESM2_ESM.tif

Supplementary file2 Supplemental Figure 2. Levels of mRNA and protein expression of wild-type and mutant SOX7 in HUVECs. Control vector (pcDNA), SOX7 wild-type (WT) alone or WT mixed with each kind of mutant plasmids (P248L, G181E and L14V) were transfected into HUVECs and harvested after 48 hours. (A) Co-transfection of WT and mutant plasmids showed higher expression of SOX7 mRNA compared to transfection of WT alone as determined by Real-time PCR (n=3). (B) Western blot demonstrated a significant decrease of SOX7 protein in the groups of co-transfection of WT and mutant plasmids as compared with the group of transfection of WT alone (n=3). (C) Real-time PCR results showed overexpression of SOX7 significantly increased the expression of ANP, BNP, MYH6 as well as NOS3 in HUVECs (n=3). *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. (TIF 21340 KB)

438_2022_1859_MOESM3_ESM.tif

Supplementary file3 Supplemental Figure 3. mRNA and protein expression of SOX7, GATA4 and GATA6 in AC16 cardiomyocytes transfected with control vector (pcDNA), SOX7 wild-type (WT) or mutant plasmids (P248L, G181E and L14V). (A) Relative mRNA expression of the wild-type plasmid and SOX7 variants in AC16 cells (n=3). (B) Western blot analysis of the control vector, wild-type and SOX7 variants in AC16 cells (n=3). (C) Relative mRNA expression of GATA4 and GATA6 in AC16 cells treated with pcDNA or SOX7 wild-type plasmids (SOX7 OE). (n=3) (D) Protein levels of GATA4 and GATA6 in AC16 cells with pcDNA or SOX7 OE (n=3). (E) Dual-luciferase reporter assays showed the activation of GATA4 promoter by SOX7 overexpression in AC16 cells (n=3). (F) Real-time PCR results indicated that overexpression of SOX7 significantly increased the expression of ANP, BNP, MYH6 as well as NOS3 in AC16 cells (n=3). # , P < 0.01 versus pCDNA; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 versus WT. (TIF 21973 KB)

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Li, B., Li, Z., Yang, J. et al. Predisposition to atrioventricular septal defects may be caused by SOX7 variants that impair interaction with GATA4. Mol Genet Genomics 297, 671–687 (2022). https://doi.org/10.1007/s00438-022-01859-5

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