Research Topics

Genetics of pulmonary arterial hypertension

In cooperation with Prof. Dr. med. Grünig at Thoraxklinik, Heidelberg University Hospital, we are searching for genetic causes of pulmonary arterial hypertension (PAH).

In the majority of patients with familial PAH, heterozygous mutations are identified in the BMPR2 (Bone Morphogenetic Protein Receptor 2) gene. In patients with sporadic, idiopatic PAH (not familial), BMPR2 mutations can be detected only in part of the cases. Apart from mutations in the BMPR2 gene, there are other genes which can be responsible for this disease, too. Among them, the following genes have been identified: ALK1 (Activin A receptor type II-like 1) and ENG (Endoglin). In families with PAH combined with Osler-Weber-Rendu disease and in patients with infantile PAH, mutations in the ALK1 gene and in the ENG gene were found. In a few cases, mutations in these two genes were detected in patients with idiopatic/hereditary PAH. Penetrance of the mutations is very variable, the factors which influence penetrance being largely unidentified. In our research cooperation, we are aiming at identifying further genes which cause PAH as well as genetic factors which modify the penetrance.

Cooperation partners:

Prof. Dr. med Ekkehard Grünig, Zentrum für Pulmonale Hypertonie, Thoraxklinik gGmbH am Universitätsklinikum Heidelberg

Staff members:

PD Dr. Christina A. Eichstaedt
Nina Wagenmann
Verena Wahl
Iris Sommer-Ort
Elke Strohmaier
Nina Litters

Repeat expansion at the FMR1 locus: Premature ovarian insufficiency

In cooperation with Prof. Dr. rer. nat. Vogt (Sektion Molekulare Genetik und Fertilitätstörungen, Frauenklinik, Universitätsklinik Heidelberg), we are looking for the genetic causes of infertility in women. In this context, at our institute we are conducting Southern Blot and PCR analyses at the FMR1 locus.

Cooperation partner:

Dr. med. Julia Rehnitz
Sektion Molekulare Genetik und Fertilitätstörungen, Frauenklinik, Universitätsklinik Heidelberg

Staff members:

Birgit Hanel
Nina Wagenmann

Functional analysis of transtyrein variants

Transthyretin (TTR) is a plasma transport protein that is mainly secreted by the liver and the choroid plexus of the brain, and carries thyroxine and retinol-binding protein. TTR is a highly conserved, ß-sheet-rich, tetrameric protein. Denatured TTR aggregates into insoluble amyloid fibers and these TTR deposits can cause systemic amyloidosis. TTR amyloidosis (ATTR amyloidosis) can be genetic or non-genetic and affects multiple organs. The genetic form is a rare disease with considerable heterogeneity. It is transmitted in an autosomal dominant fashion. TTR variants are usually generated by amino acid substitutions. These variants are thought to be responsible for hereditary ATTR amyloidosis. Single point mutations can increase the likelihood of TTR misfolding into insoluble ß-pleated sheets, which can accumulate in the extracellular spaces of various organs and tissues. These deposits have been found in heart, nerves and other tissues, causing hereditary ATTR amyloidosis with cardiomyopathy or polyneuropathy.

Destabilization and dissociation of the TTR tetramer promotes unfolding and subsequent misfolding of monomers and fibril aggregation, and is thought to be the cause of variant amyloidogenicity. Although many variants have already been described in the last decade (http://amyloidosismutations.com/) unclassified variants are still being discovered. Further characterization is required to determine whether these variants are disease-associated or benign. To functionally characterize unclassified TTR variants we are using a simplified, validated, and reproducible IEF analysis (Hinderhofer et al. 2019, Amyloidosis 26:85‐93).  

Cooperation partners:

Prof. Dr. med. Ute Hegenbart und Prof. Dr. med. Stefan Schönland, https://www.klinikum.uni-heidelberg.de/interdisziplinaere-zentren/amyloidose-zentrum, Universitätsklinikum Heidelberg

Staff members:

Iris Sommer-Ort