If the Heart Does not Beat on the Left Side
Heterotaxy and Congenital Heart Disease
Scientific name of the study
1. Identification and analysis of genetic variants of GPCR-Kinase-5 in connection with heterotaxy
2. Effect of mitochondria amount on the development of left-right asymmetry of the heart
“To have one’s heart in the right place,” is what we use to say colloquially to refer to someone behaving in a good way. Strictly speaking, however, the heart is located on the left side of the chest in healthy individuals.
The Organs Are Placed in Other Locations
There are also people, however, whose organs are assembled exactly the other way around. One in about 8,500 people is affected by heterotaxy, as this condition is called. Taking a major city such as Frankfurt a. M. as an example, this would statistically apply to over 80 people. This disease is referred to as situs inversus, which means that the heart and all the other organs are asymmetrically mirrored from their normal positions. In certain individuals, the order of the inner organs is in fact completely disarranged. Patients with so-called situs inversus or heterotaxy, respectively, can be recognized by the fact that each organ seems to pick its own place in the body regardless of the other organs. The distribution of the heart, liver, spleen, as well as the position of the intestinal coils, are random. And this is what usually causes complications.
Diagnosis is already Established during Pregnancy
Heterotaxy is frequently diagnosed at a very early stage. It is established during pregnancy, or, if this is not the case, shortly after birth. Newborns in which the inner organs are randomly assembled often have a bluish skin, do not drink well and have breathing difficulties. These symptoms could be caused by congenital heart disease which affects almost every child with heterotaxy.
Gene Mutations Might Be Responsible
Although congenital heart disease occurs relatively frequently, the causes are still not entirely clear even today. It is certain, however, that a considerable proportion has a genetic cause. Accordingly, mutations in certain genes can be the cause of an abnormal heart development. This mostly applies to genes that are heart-specific. In certain cases, however, it does not necessarily have to be a gene from right within the heart that guides the heart’s development.
The Body has to be Able to Know the Difference between Right and Left
At a very early stage during development, the body axes are defined. This determines the outer and inner form of our body. In this context, the normal development of the left-right axis and, accordingly, of an inner asymmetry, is important particularly for the development and placement of the heart. If the body does not know where its left and right side will be, this will lead to complications in the organs’ placement that are not visible from the outside. In particular, this can result in heart malformations, that is, congenital heart disease.
Donated Data from the Register Support our Research
At the University of Ulm, we are investigating the development of such heart defects that are caused by an irregular determination of left and right in the body. By means of the DNA of heterotaxy patients that is stored in the biorepository of the National Register for Congenital Heart Defects, we are looking for mutations in a gene that is essential for the functioning of adult hearts. Preliminary tests have revealed that this gene plays quite a significant role in the determination of the organ asymmetry and, above all, in the development of the heart.
Changes in GRK5
Preliminary Results of the Study
In a first step, the research team led by Melanie Philipp was able to identify changes in the protein-coding gene GRK5 that are evidently involved in the development of heterotaxy. The zebrafish was used as a model for the study.
Read more about the preliminary results of the study here:
The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5.
Lessel D, Muhammad T, Casar Tena T, Moepps B, Burkhalter MD, Hitz MP, Toka O, Rentzsch A, Schubert S, Schalinski A, Bauer UMM, Kubisch C, Ware SM, Philipp M
Scientific reports 6, 33231, (2016). Show this publication on PubMed.
Failure in the Cell’s Powerhouses
As of May 2019, the results of the investigations in mitochondria have been available. With respect to the development of heterotaxy, these powerhouses of the cells play a larger role than previously known.
Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis.
Burkhalter MD, Sridhar A, Sampaio P, Jacinto R, Burczyk MS, Donow C, Angenendt M, , Hempel M, Walther P, Pennekamp P, Omran H, Lopes SS, Ware SM, Philipp M
The Journal of clinical investigation 130, 2841-2855, (2019). Show this publication on PubMed.
In charge of the project:
Melanie Philipp is the Head of the Department of Pharmacogenomics at the Institut für Experimentelle und Klinische Pharmakologie und Pharmakogenomik at the University Hospital of Tübingen. More
Melanie Philipp first studied pharmacy at the University of Würzburg. After obtaining her license to practice pharmacy, she did her doctorate at the Institut für Pharmakologie und Toxikologie at the University of Würzburg. Her research interests first brought her to Switzerland, where she worked with the Zoologisches Institut of the University of Zurich. Later, she transferred to the Department of Cell Biology at Duke University Medical Center in Durham, North Carolina, USA, before she moved to Ulm, where she led the junior research group at the Institute for Biochemistry and Molecular Biology (IBMB) at the University of Ulm until 2019. After having been the head of the Department of Pharmacogenomics at the Institut für Experimentelle und Klinische Pharmakologie und Pharmakogenomik, Melanie Philipp, who is both a pharmacist and habilitated biochemist, transferred to the Eberhard Karls University of Tübingen in 2019. She is a member of the Competence Network for Congenital Heart Defects.