Patients diagnosed with hearing loss due to variants in the otoferlin gene, or OTOF, can now participate in a specific registry at the University Medical Center Göttingen (UMG). The registry, which is administrated in a collaboration by the Institute of Human Genetics and the Institute of Auditory Neuroscience, connects patients with scientists that are experts in the research into various forms of hearing loss, their genetic basis and potential new approaches for their treatment.

The database is open to affected adults and children/adolescents (with their parents‘ consent). Information will be collected on the participant’s medical history, the natural history of the hearing impairment, the treatment, and relevant genetic data of the affected person. Data will be pseudonymized, processed and stored in accordance with the European General Data Protection Regulation. The study is led by PD Dr. Barbara Vona and aims at providing new insights into the mechanisms leading to this specific form of hearing loss and contributing to the development of new therapeutic approaches. Participants may choose to be contacted in the future to receive information about available clinical studies and therapeutic options at the UMG.

Hearing impairment belongs to the most common congenital conditions. Most cases of congenital hearing loss are due to genetic defects, and thousands of variants in hundreds of genes have been found to be responsible for hearing loss. One of these genes is OTOF. It contains the genetic information to produce otoferlin, a protein contained in the auditory sensory cells of the inner ear and is essential for transmitting acoustic signals from the inner hair cells to the auditory nerve cells.

Patients who wish to participate in the registry are invited to download an information leaflet from a specific registry website. Using a secured online system, they can then complete a consent form and a questionnaire. If they wish they can also upload clinical documentation like hearing test and genetic test findings.

The registry study has been approved by the Ethics Committee of the University Medical Center Göttingen.

Contact: PD Dr. Barbara Vona, barbara.vona@med.uni-goettingen.de

Congenital rare skeletal disorders are conditions that affect the development and growth of bone and cartilage tissue. In most cases they are genetic in nature. They manifest either as skeletal malformations alone or as characteristic combinations of symptoms that can also involve other tissues. In a collaboration led by Professor Uwe Kornak at the Institute of Human Genetics Göttingen, research teams from Germany, Austria, the Netherlands, Saudi Arabia, and the U.S. have discovered the genetic cause of a previously undescribed specific skeletal disorder. In their study, they identified homozygous variants in the AXIN1 gene in seven patients ranging in age from three months to 15 years old. Radiologically and clinically, these patients presented with a phenotype characterized by generally elevated bone mineral density, excessive skull bone tissue, abnormally large head size (macrocephaly), hip joint malformation, and a developmental delay of variable degree.

The researchers performed additional investigations in different cell models to explore the consequences of the identified variants. This included patient-derived cells as well as cells in which they intentionally introduced the detected AXIN1 variants through genome editing. Their analyses showed that these genetic changes resulted in a smaller amount of functional AXIN1 protein and an enhanced activation of the Wnt signaling pathway.

AXIN1 is a crucial component in the regulation of the beta-catenin-dependent Wnt signaling pathway. This signaling cascade controls fundamental cellular processes during embryonic development and also plays an important role in the balance of bone formation and resorption. AXIN1 has been the subject of extensive research, but no germline variants of this gene have been reported in humans to date. The results of the recent study, published in the American Journal of Human Genetics, suggest that AXIN1 influences the activity of osteoblasts and osteoclasts. These two cell types work together in an intricately coupled manner: osteoblasts form bone tissue while osteoclasts destroy it.

Rare skeletal disorders, their genetic causes and underlying molecular mechanisms and the development of specific gene therapy approaches are a key focus of the Kornak research group at the Institute of Human Genetics Göttingen. New insights gained from their research are directly translated into clinical care at the University Medical Center Göttingen: “In our specialized Center for Rare Skeletal Diseases patients and their families receive individual counselling as well as fast clinical, laboratory, and molecular genetic diagnostics and they have access to specific treatment options. With our research, we aim at advancing the development of new therapeutic approaches and their direct integration into clinical practice”, says Professor Kornak.

AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia
Terhal P, Venhuizen AJ, Lessel D, Tan WH, Alswaid A, Grün R, Alzaidan HI, von Kroge S, Ragab N, Hempel M, Kubisch C, Novais E, Cristobal A, Tripolszki K, Bauer P, Fischer-Zirnsak B, Nievelstein RAJ, van Dijk A, Nikkels P, Oheim R, Hahn H, Bertoli-Avella A, Maurice MM, Kornak U.
Am J Hum Genet 2023 Aug 9:S0002-9297(23)00251-3. doi: 10.1016/j.ajhg.2023.07.011. Epub ahead of print.

New insights into how senescent cells play a role in wound healing not only through its secretory action but also by impacting on cell mechanics have been provided by a study performed at Charité Universitätsmedizin Berlin and published in Aging Cell. Led by Uwe Kornak, professor at the Institute of Human Genetics Göttingen, and Ansgar Petersen, professor at Julius Wolff Institute of Charité, a team of scientists has revealed that cellular senescence beneficially influences tissue formation by modulating cell mechanics and extracellular matrix (ECM) synthesis and composition.

Senescence is a multistep process in which cells, in response to different stresses and damage, go from a transient cell cycle inhibition to an irreversible state in which they no longer divide. Senescent cells do not die but remain metabolically active, secreting a characteristic combination of proteins and factors that can affect the cell’s surrounding environment, the extracellular matrix, and neighboring cells. Accumulation of senescent cells is a hallmark of ageing and a factor in the development of ageing-associated pathologies. These detrimental effects are also investigated intensively at the Institute of Human Genetics. There is, however, also a positive aspect of cellular senescence: Short-term presence of senescent cells promotes wound healing and contributes to scar development. However, it has so far not been known that senescence has also a direct role in tissue formation beyond its paracrine signaling.

The researchers used a specific in vitro wound healing model of primary human skin fibroblasts in which they induced cellular senescence by two different mechanisms (either by DNA damage or by overexpression of cell cycle inhibitors). They investigated the effects of both types of senescence on cell migration, morphology and adhesion. Their investigations showed that cellular senescence modulated size and composition of focal adhesions. These multiprotein structures anchor cells to the extracellular matrix and are responsible for transferring cellular forces. In all senescent cells, increased single cell forces were observed. However, in DNA damage-mediated senescence, contrary to senescence induced by cell cycle inhibitors, degenerative changes in ECM acted against contraction in 3D cell cultures. Thus, depending on the type, senescence showed different and partly conversing effects on tissue formation, contraction and tensioning. In addition to mechanical effects, the study also revealed altered expression profiles for genes encoding ECM-related proteins including collagens, lysyl oxidases and matrix metalloproteinases.

Contact: Prof. Dr. med. Uwe Kornak, uwe.kornak@med.uni-goettingen.de