TY - JOUR
T1 - A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A
AU - Demal, Till Joscha
AU - Heise, Melina
AU - Reiz, Benedikt
AU - Dogra, Deepika
AU - Brænne, Ingrid
AU - Reichenspurner, Hermann
AU - Männer, Jörg
AU - Aherrahrou, Zouhair
AU - Schunkert, Heribert
AU - Erdmann, Jeanette
AU - Abdelilah-Seyfried, Salim
PY - 2019/12/1
Y1 - 2019/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85062258921&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-39648-7
DO - 10.1038/s41598-019-39648-7
M3 - Journal articles
C2 - 30814609
AN - SCOPUS:85062258921
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 2959
ER -
