A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A

Till Joscha Demal; Melina Heise; Benedikt Reiz; Deepika Dogra; Ingrid Brænne; Hermann Reichenspurner; Jörg Männer; Zouhair Aherrahrou; Heribert Schunkert; Jeanette Erdmann; Salim Abdelilah-Seyfried

doi:10.1038/s41598-019-39648-7

A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A

Till Joscha Demal, Melina Heise, Benedikt Reiz, Deepika Dogra, Ingrid Brænne, Hermann Reichenspurner, Jörg Männer, Zouhair Aherrahrou, Heribert Schunkert, Jeanette Erdmann^*, Salim Abdelilah-Seyfried

^*Korrespondierende/r Autor/-in für diese Arbeit

16 Zitate (Scopus)

Abstract

The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein’s anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aa ^p.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.

Originalsprache	Englisch
Aufsatznummer	2959
Zeitschrift	Scientific Reports
Jahrgang	9
Ausgabenummer	1
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-019-39648-7
Publikationsstatus	Veröffentlicht - 01.12.2019

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We thank R. Aherrahrou, S. Wrobel, C. Otten, V. Lombardo, A.-C. Dietrich, S. Donat, J. Richter, and S. Kraft for their advice on experimental protocols and for providing fish stocks, reagents or other support. Thanks to A. Tafazzoli and M. Wehle for their help in blinding our studies. We also thank Dr. Reinhard Vonthein (Institut für Biometrie und Statistik, University of Lübeck, Lübeck, Germany) and Dr. Maren Vens (Institut für Medizinische Biometrie und Epidemiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany) for their advice on the statistical analysis of our studies. We thank Lisanne Maibücher for proofreading of the manuscript. This work was supported by the Excellence cluster REBIRTH and the DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.). T.D. was supported by the Kaltenbach grant of the Deutsche Herzstiftung e.V., the scholarship “Lübecker Exzellenzmedizin” of the University of Lübeck, and a travel grant of the mobility program of the DZHK. M.H. was supported by a fellowship of the Excellence cluster REBIRTH and by a fellowship by the Joachim Herz foundation. S.A.-S. was supported by the Excellence cluster REBIRTH, SFB958, and by Deutsche Forschungsgemeinschaft (DFG) projects SE2016/7-2 and SE2016/10-1.

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10.1038/s41598-019-39648-7

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title = "A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A",

abstract = " The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM\_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein{\textquoteright}s anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aa p.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/{\ss}-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology. ",

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AU - Brænne, Ingrid

AU - Reichenspurner, Hermann

AU - Männer, Jörg

AU - Aherrahrou, Zouhair

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - Abdelilah-Seyfried, Salim

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N2 - The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein’s anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aa p.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.

AB - The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein’s anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aa p.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.

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A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A

Abstract

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