News

In today’s issue of Lübecker Nachrichten, our local daily newspaper, an article was published about our work on collagen-6 myopathy.

Raising awareness for rare diseases is extremely important. As a patient affected with a rare disease (Collagen 6 congenital muscular dystrophy) Jeanette Erdmann, director of the ICG, wants to spread the word about help and information, including potential therapies.

To achieve this Jeanette Erdmann candidated sucessfully for chairman of the Landesverband Schleswig-Holstein of the Deutsche Gesellschaft für Muskelkranke e.V (DGM).

The DGM (www.dgm.org) was founded in 1965 as a parent initiative supported by doctors and business people.

At that time, the primary goal was to research and combat muscle diseases (DGBM), which is why the society was initially called “Deutsche Gesellschaft Bekämpfung der Muskelkrankheiten” (German Society for Combating Muscle Diseases).

Over the years, the range of tasks has greatly expanded and the idea of self-help has gained in importance. Not only to promote research, but at the same time to support those affected and their relatives on their way with a muscle disease, this is still one of the most important goals of our organization. For this reason, since 1993 it has been called the German Society for Muscle Diseases (Deutsche Gesellschaft für Muskelkranke e.V.). (DGM).

Today the DGM has more than 8000 members and is therefore not only the oldest but also the largest self-help organisation for people with neuromuscular diseases in Germany. The DGM offers its members advice, help and the opportunity to exchange experiences with other patients. In addition, the DGM is committed to the interests of those affected in the field of health policy and specifically promotes research in the field of neuromuscular diseases.

Experts estimate that more than 100,000 people in Germany are affected by a neuromuscular disease. There are currently around 800 different known diseases, each of which is rare, in some cases extremely rare. The majority of neuromuscular diseases are hereditary and unfortunately still incurable today. For those affected, such a disease primarily means the progressive loss of their mobility. Everyday activities become hard work and can only be mastered with the help of outside help and appropriate aids. Depending on the disease, those affected have to struggle with organic weaknesses and have to reckon with a drastically shortened lifetime. Some illnesses have a considerable impact on the lives of those affected even in childhood. Other illnesses only occur in adulthood and tear the affected people and their families out of their normal lives.

Since there is no cure for these illnesses, the preservation of quality of life, the individual adaptation of soothing therapies and the optimal provision of aids are particularly important for those affected. In addition to the ever increasing physical limitations, the examination of such a diagnosis is often mentally very stressful for those affected and their families. In addition, there are often lengthy discussions with health insurance companies and other payers.

People with muscle diseases hardly have a lobby. In most cases, the diseases are too rare to be of interest for pharmaceutical-funded research. Patients not only have to learn how to deal with the disease, but also have to explain their illness to an often ignorant environment. The DGM offers patients a wide range of support and advice, initiates research and carries out important public relations work to make these diseases better known.

People with muscle diseases need your help. By supporting the DGM in its work, you can help them.

The Research Topic: “From GWAS hits to treatment targets” was accompanied by a symposium held in Lübeck on January 12th, 2018. The agenda and pics can still be found here.

About the Research Topic:

Genome-wide association (GWA) studies, as a prototype of large-scale OMICs studies, have advanced our understanding of the genetic basis of many common diseases. With respect to coronary artery disease (CAD) and cardiovascular risk factors, like lipids, blood pressure or BMI, they have identified hundreds of chromosomal loci that modulate disease risk. Despite their scientific success, GWA studies have been criticized for having failed so far in delivering diagnostically or therapeutically relevant products.
However, the ability to achieve such goals has been strengthened recently by further layers of OMICs-based data, including large-scale transcriptomics data, and better annotation of regulatory sequences and epigenetic changes in the genome (e.g. through the ENCODE project), as well as novel tools for bioinformatics analysis, allowing a systems medicine based approach to be applied.

All in all, the last decade with its “gold rush of genomic discovery” led to the identification of known and novel pathways involved in the pathogenesis of cardiovascular diseases and point to novel treatment targets.

The aim of this Research Topic was to gather contributions from scientists working in the field of cardiovascular genetics who have common interests in understanding the pathomechanisms linking genetic association findings and disease to finally translate the findings from large-scale genetic studies into novel treatment options.

The Research Topic: “From GWAS hits to treatment targets” can now be downloaded as an eBook.

Effective Mid August 2019 until End of July 2021, Jeanette Erdmann joined the team of Circulation: Genomic and Precision Medicine as Senior Guest Editor. The new Editor-in-Chief is Prof Chris Semsarian.

About Circulation: Genomic and Precision Medicine (from the website)

The journal considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease.

We are waiting for your papers: https://circgen-submit.aha-journals.org/cgi-bin/main.plex

Mithilfe modernster Genanalysemethoden konnte ein deutsches Forscherteam zeigen, dass ein komplexer angeborener Herzfehler seinen Ursprung in mehreren Genen hat und wie diese Genveränderungen zusammenwirken. Das Team untersuchte dafür über viele Jahre eine 19-köpfige Familie, in der zwölf Personen von einer bestimmten Genveränderung betroffen sind. Die Ergebnisse der Studie präsentieren die Forscherinnen und Forscher in Scientific Reports.

Angeborene Herzfehler sind die häufigsten Organfehlbildungen und kommen bei circa einem Prozent der Neugeborenen vor. Die Fehlbildungen des Herzens lassen sich immer besser behandeln, weshalb sich Betroffene zunehmend dafür entscheiden, selbst eine Familie zu gründen. Mediziner und Biologen interessieren sich aus diesem Grund wieder mehr für die molekularen Ursachen dieser Erkrankungen, um die therapeutischen und auch diagnostischen Möglichkeiten zu verbessern.

Zusammenspiel mehrerer Genveränderungen

An Fehlbildungen des Herzens sind eine Vielzahl von Genen beteiligt. Nur eine geringe Anzahl dieser Erkrankungen wird durch Mutationen in einzelnen Genen, sogenannten monogenen Mutationen, verursacht. Als Gen bezeichnet man eine Code-Abfolge in der Erbsubstanz DNA, die den Bauplan für ein Protein enthält. Die Vermutung liegt nahe, dass zahlreiche angeborene Herzerkrankungen durch das gleichzeitige Auftreten von Mutationen in unterschiedlichen Genen verursacht werden. Eine der dringendsten Herausforderungen bei der Suche nach den Ursachen von angeborenen Herzfehlern ist es somit, das Zusammenspiel dieser vielfachen Genveränderungen besser zu verstehen.

Das Forscherteam aus Deutschland konnte nachweisen, dass Familienuntersuchungen mittels modernster DNA-Sequenziertechnik geeignet sind, auch komplexe, sprich multigene, Ursachen zu identifizieren. Anschließend modellierten sie diese Genveränderungen im Zebrafisch und konnten so zeigen, wie diese sich auf das Herz auswirken.

Die beteiligten Wissenschaftlerinnen und Wissenschaftlern des Universitätsklinikums Hamburg-Eppendorf, der Medizinischen Hochschule Hannover, des Deutschen Herzzentrums München, der Universitätsmedizin Göttingen, der Universität zu Lübeck sowie der Universität Potsdam präsentieren in der Studie die Sequenzierungsdaten einer Familie mit unterschiedlichen komplexen angeborenen Herzfehlern, einschließlich der Ebstein-Anomalie, dem atrioventrikulären Septumdefekt und anderen. Insgesamt zwölf von 19 Familienmitgliedern tragen eine familienspezifische Mutation im BMPR1A-Gen auf Chromosom 10. Diese Mutation geht einher mit einer bislang unbekannten Mutation innerhalb einer Region des Chromosom 1 und führt zur Entstehung dieser schweren Herzfehlbildungen.

Kleinere Herzklappen beim Zebrafisch

Das Rezeptorprotein BMPR1A und seine Liganden sind an der Übertragung chemischer Signale von der Zellmembran zum Kern beteiligt und regulieren somit das Zellwachstum und die Zellteilung sowie die Aktivität bestimmter Gene. Im Zebrafisch konnte nun gezeigt werden, dass die kontinuierliche Überexpression der menschlichen BMPR1A-Mutation mit der Entwicklung kleinerer Herzklappen assoziiert ist, zur Herabregulation des für die Herzentwicklung so wichtigen Wnt/ß-Catenin-Signalwegs führt und zudem Gewebswucherungen an den Herzklappen verursacht. Dies ist ein Zeichen dafür, dass BMPR1A an der Herzentwicklung beteiligt ist.

Dieser Befund eröffnet die Möglichkeit, die genetische Interaktionen zwischen BMPR1A und anderen Kandidatengenen innerhalb der Region auf Chromosom 1 zu testen und damit komplexere genetische Ursachen für angeborene Herzfehler aufzuspüren.

Moderne Sequenzierungsverfahren brachten den Durchbruch

Prof. Jeanette Erdmann von der Universität zu Lübeck erläutert: „Die Studie ist auch ein Paradebeispiel für Ausdauer in der Forschung, denn die Anfänge datieren zurück ins Jahr 1996, als die erste Patientin aus der Familie vorstellig wurde. Nur durch die rasante technologische Entwicklung der letzten Jahre, hier vor allem das sogenannte Next-Generation-Sequencing-Verfahren, konnte die Studie positiv abgeschlossen werden. Zudem war natürlich auch die Geduld der Familie unabdingbar“.

Prof. Salim Seyfried von der Universität Potsdam ergänzt: „Die Untersuchungen am Zebrafisch waren letztendlich entscheidend, um die Krankheitsrelevanz der Kandidatenmutation nachzuweisen. Diese vom Deutschen Zentrum für Herz-Kreislauf-Forschung geförderte Kooperation belegt, wie wichtig heutzutage das Zusammenwirken von Arbeitsgruppen mit unterschiedlichsten Expertisen für die moderne arbeitsteilige Biomedizin geworden ist.“

Das Projekt wurde in den vergangenen Jahren von dem Exzellenzcluster REBIRTH, dem Deutschen Zentrum für Herz-Kreislauf-Forschung (DZHK), der Universität zu Lübeck, der Deutschen Herzstiftung sowie der DFG gefördert.

Wissenschaftliche Ansprechpartner:

Prof. Dr. Salim Seyfried
MHH-Institut für Molekularbiologie und Universität Potsdam
Telefon (0511) 532 5933 oder (0331) 977 5540
Salim.Seyfried@uni-potsdam.de

Prof. Dr. Jeanette Erdmann
Universität zu Lübeck / UKSH, Campus Lübeck
Institut für Kardiogenetik
Telefon: (0451) 3101 8300
jeanette.erdmann@uni-luebeck.de

Originalpublikation:

A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A. Scientific Reports (2019)

https://www.nature.com/articles/s41598-019-39648-7

Great news for our institute and the whole consortium!

We succeeded to get funded jointly by the BHF and DZHK (2.4 Mio € in total for 4 years).

In 2018, for the first time, the British Heart Foundation (BHF) and DZHK came together to create a partnership research funding scheme to encourage international collaboration between cardiovascular researchers in the UK and Germany.

The aim was to fund innovative cardiovascular research with the potential for improved clinical diagnosis, prevention or treatment.

Together with colleagues from Munich (Heri Schunkert, Christian Weber) and UK (Shu Ye, John Danesh) Hugh Watkins and I will work on “Genetic discovery-based targeting of the vascular interface in atherosclerosis”.

This collaborative project aims to help understand how our genes affect our risk of heart disease. Studies involving large groups of people with and without heart disease have identified changes in the DNA code that are more frequent in people with the disease. We found many of these DNA changes are in genes involved in the wall of our blood vessels, an essential biological system in the development of heart disease. We will combine innovative computational and experimental methods to investigate these genes in great detail to understand how exactly they affect disease risk, and to translate this knowledge into new treatments (lay summary taken from grant application).

Over the next couple of months several papers co-authored by the gnomAD PIs, the Genome Aggregation Database Production Team and the Genome Aggregation Database Consortium will be submitted to biorxiv and in parallel for peer-review to high-impact journals.

We are happy to announce that the ICG is part of the Genome Aggregation Database Consortium. More information can be found on our blog.

https://iieglabletters.blogspot.com/2019/01/honored-to-be-part-of-gnomad-consortium.html

This project is a prime example of perseverance. Finally, after 20 years of work we were able to unravel the multigenic origin of a congenital heart disease in an extended family.

Originally, this family was recruited in 1996 (!) and published in 1997 by Heri Schunkert and colleagues (link to pubmed).

In 1999, we performed linkage analysis with microsatellite markers and identified a locus on chromosome 1. However, extensive candidate gene sequencing by Sanger revealed no pathogenic variant within this linkage region.

Several years later we decided to perform whole-exome and whole-genome sequencing in this family to get an answer finally.

Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328G>A (p.R443H)] which encodes a predicted variant of BMPR1A. This mutation co-segregates with the linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein’s anomaly, atrioventricular septal defect, and others. Unfortunately, we were not able to pinpoint a genetic variant on chromosome 1 that could explain the phenotypes.

However, we started with functional studies in zebrafish and could 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 now the possibility of testing genetic interactions between BMPR1A and other candidate genes within the linkage region on chromosome 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.

The project involved many people at different places, former PhD and MD students. Overall, we had a very complimentary collaboration, starting with classical linkage analysis, old-fashion and next-generation sequencing, and state-of-the-art zebrafish work.

In Lübeck my thanks go to Till, Benedikt, Ingrid, and Zouhair! My very special thanks go to Salim and Melina and their team members. The project could not have been completed without their help.

Now, we are looking forward to Till´s MD thesis defense.

In Lübeck my thanks go to Till, Benedikt, Ingrid, and Zouhair! My very special thanks go to Salim and Melina and their team members. The project could not have been completed without their help.

Now, we are looking forward to Till´s MD thesis defense. 

And we hope to get funding for a follow-up study to shed more light into the link between BMPR1A mutation on chromosome 10 and the linkage region on chromosome 1. This project is not at its end.

The pdf of this manuscript can be found here.