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Developing personalized therapy strategies for pancreatic cancer: UMG receives DFG funding

Developing new and specific therapeutic options for pancreatic cancer (PDAC) is the overall goal of a new Clinical Research Unit at the University Medical Center Göttingen, to which the German Research Foundation (DFG) has now granted nearly 5.9 million Euros in funding for a period of four years. The researchers of KFO 5002 “Deciphering genome dynamics for subtype-specific therapy in pancreatic cancer” are investigating the mechanistic and functional effects of deregulated genome dynamics, e.g. defects in genome stability, chromosome structure/function or DNA transcription. Their aim is to find out how these effects lead to specific features of different PDAC subtypes in terms of their progression and resistence and to use these new insights to develop novel and personalized therapeutic options. KFO 5002 has started its research activities in September and is coordinated by Prof. Volker Ellenrieder (Director Department of Gastroenterology and Gastrointestinal Oncology) and PD Dr. Elisabeth Heßmann (Department of Gastroenterology and Gastrointestinal Oncology).

The Institute of Human Genetics contributes significantly to KFO 5002 in two essential core projects that support the experiments performed in the different scientific subprojects. A multigene panel comprising 82 PDAC-associated genes has been specifically designed for the clinical research unit and is applied for molecular characterization of tumor samples by highthroughput sequencing (PD Dr. Silke Kaulfuß, Prof. Bernd Wollnik). NIG, the NGS Integrative Genomics Core Unit affiliated with the Institute and headed by Dr. Gabriela Salinas, performs next-generation sequencing-based transcriptome analyses for all CRC partners to decipher subtype-specific signatures.

PDAC is one of the most common tumors and has a very poor prognosis. It is an exceptionally aggressive type of cancer showing a remarkable therapeutic resistance. Therefore, innovative and better treatment strategies are desperately needed to improve survival rates of patients with pancreatic cancer.

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Common genetic cause of unclear disorder in three children uncovered

Researchers at the Institute of Human Genetics Göttingen have uncovered the genetic cause of a previously undescribed disorder associated with a combination of several malformations and intellectual disability. Surprisingly, their patients, three unrelated children, come from the same geographical region. Relatively little is known so far about the function of the identified gene, FBRSL1.

A study led by researchers of the Institute of Human Genetics at the University Medical Center Göttingen has uncovered the genetic cause of a new and complex syndromic disorder. Three children showed an overlapping clinical picture with a severe developmental delay, respiratory and swallowing problems, growth retardation, joint contractures, dysmorphic facial features and other malformations like heart defects. Two of the children had a particularly striking feature: distinctive skin creases, predominantly on the back, which were present at birth but decreased during the first year of life. This specific combination of features had not been described before. To find the underlying cause of the disorder and to provide the affected families with a precise diagnosis, the researchers performed exome sequencing. This molecular genetic tool allows to analyze in a single step all parts of a patient’s DNA that contain information required to make proteins. The researchers found that all three children carried a variant of the FBRSL1 gene. This gene and its encoded protein have so far not been investigated in detail.

“Usually, when we try to find a genetic defect that underlies an unclear disorder, we only have a single patient and his or her parents. If we find a candidate gene, the next step must then be to look for other patients who are similarly affected. This is quite challenging for a rare disorder which affects perhaps only a few patients across the globe”, says Professor Silke Pauli, research group leader at the Institute of Human Genetics Göttingen and senior co-author of the study. “Here, with three affected children, unrelated and coming from the same region, we have a rather unusual situation. It makes us assume that the disorder is not so very rare after all and might be present in more patients than previously appeared”.

To explore how the identified genetic changes affect cellular and molecular processes, the researchers performed various cell and animal experiments together with their collaboration partner Professor Annette Borchers and her team at the University Marburg. Their results suggest that a reduction in protein function during embryogenesis leads to a disturbance in neurodevelopment. In a project funded by the German Research Foundation (DFG), Professor Pauli and her team will now continue to gain deeper insights into the role of FBRSL1 in the development of the disease.

The study has been published in Human Genetics.

De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome.
Ufartes R, Berger H, Till K, Salinas G, Sturm M, Altmüller J, Nürnberg P, Thiele H, Funke R, Apeshiotis N, Langen H, Wollnik B, Borchers A, Pauli S.
Hum Genet. 2020 May 18. doi: 10.1007/s00439-020-02175-x. Online ahead of print.

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Brittle bone disease: Novel gene provides clue to potential therapeutic approach in the future

Extremely fragile bones are the reason why mainly children, but also adults with brittle bone disease will frequently break their bones, often even without any apparent injury. The genetic disease, also called osteogenesis imperfecta (OI), may present in varying forms from mild to severe and can also be associated with other symptoms including short height, hearing loss, skeletal deformity, loose joints, impaired vision and others. OI is a rare disease and affects 4 to 7 in 100.000 people. So far, a number of genes have been described in which defects might lead to disturbed bone formation and to the development of OI. Nevertheless, in some patients the underlying genetic cause remains unclear.

Led by the research group of Bernd Wollnik, Director of the Institute of Human Genetics at the University Medical Center Göttingen (UMG), a collaboration of scientists from Germany, Brazil, Portugal, UK and Switzerland has now discovered a novel gene involved in the development of OI. They studied five patients with progressive skeletal deformities who had suffered multiple bone fractures before their second year of life or even before birth, and they identified mutations in a novel gene: MESD. “We performed whole-exome sequencing in all patients, which means, we analyzed all coding regions of all 19.000 genes of the human genome in parallel. Before doing so, we had checked whether the patients carried any potentially disease-causing variations in genes that we already know to be connected with OI. They did not – but instead we discovered that they all had a mutation in both copies of the MESD gene. MESD has never before been linked to a human disorder, but we knew that it is involved in the WNT signaling pathway. This made it an excellent candidate for us”, describes Bernd Wollnik.

The WNT signaling pathway is a major network of various molecules and regulates fundamental cellular processes including embryonic development, cell differentiation and cell division. Although MESD is not a direct component of the WNT pathway, it acts indirectly within this network. As a chaperone protein it ensures that specific WNT receptor molecules, LRP5 and LRP6, adopt the protein folding they need for their correct functioning and that they traffic from the endoplasmatic reticulum to the cell membrane.

The researchers also performed detailed experiments in different animal models to elucidate the functional consequences of the identified mutation in cells. They showed that, due to their specific position in the protein, the mutations led to a reduction of MESD function but not to a complete loss. The role of WNT signaling in bone growth and strength had already been known. The Wollnik research group had in a previous study several years ago also demonstrated that a protein called WNT1, another component in this pathway, is relevant for bone formation and bone cell function.

So far there is no cure for OI. Therapy is based on surgery, physical therapy and medical treatment with bisphosphonates. However, in the current study, the use of bisphosphonates did not produce any positive effect. For Bernd Wollnik, this study also opens new perspectives for the treatment of OI: “Our cell experiments hint to a novel approach: Biological agents activating WNT signaling might be a potential treatment option for patients with MSED-associated OI.” Such a drug is already available and used to treat patients with aging-associated osteoporosis to increase bone formation and bone mass.

Bernd Wollnik and his research group at the Institute of Human Genetics in Göttingen have been intensively working on elucidating the genetic causes and molecular mechanisms of rare diseases. Their research focuses especially on disorders with premature aging (progeroid diseases), microcephalies and the biological processes underlying genomic instability.

The results of the current study have been published in The American Journal of Human Genetics.

Autosomal Recessive Mutations in MESD Cause Osteogenesis Imperfecta.
Moosa S, Yamamoto GL, Garbes L, Keupp K, Beleza-Meireles A, Moreno CA, Valadares ER, de Sousa SB, Maia S, Saraiva J, Honjo RS, Kim CA, Cabral de Menezes H, Lausch E, Lorini PV, Lamounier A Jr, Carniero TCB, Giunta C, Rohrbach M, Janner M, Semler O, Beleggia F, Li Y, Yigit G, Reintjes N, Altmüller J, Nürnberg P, Cavalcanti DP, Zabel B, Warman ML, Bertola DR, Wollnik B, Netzer C.
Am J Hum Genet. 2019 Sep 20. pii: S0002-9297(19)30312-X. doi: 10.1016/j.ajhg.2019.08.008. [Epub ahead of print]

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NIG: Modern integrated genomics is a key element to innovative research and personalized medicine

Genomics, epigenomics and transcriptomics are crucial elements in modern biomedical research towards personalized medicine. Next-generation sequencing, the technology that allows to simultaneously analyze millions of DNA or RNA molecules, is a powerful tool that opens new research horizons. NIG, the NGS Core Unit for Integrated Genomics at the University Medical Center Göttingen (UMG), is an internationally recognized service provider that delivers a broad portfolio of the latest technologies and methods to research groups and offers its users flexible and cost-efficient NGS applications within modern research approaches.

“Here at NIG, we have the longstanding expertise, first-rate technical equipment and refined infrastructure needed to successfully realize research projects. Our users benefit from a comprehensive service ranging from project design and selection of suitable methods to performing a broad range of state-of-the-art NGS-based experiments. In addition, we can also provide extensive statistical and bioinformatics support throughout the process, from assisting with experimental design to analyzing the generated experimental data” explains Dr. Gabriela Salinas, Head of NIG.

Prof Bernd Wollnik, Director of the Institute of Human Genetics, to which NIG is functionally affiliated, sees NIG as a key element and driver within UMG’s research structure: “This core unit delivers high-quality NGS data to researchers who analyze them by means of complex algorithms and bioinformatics pipelines to extract important insights into the processes that take place in specific biological systems, signaling pathways and organs. These methods and findings are central to the progress of personalized medicine.”

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Hallermann-Streiff syndrome: The molecular link of the well-known syndrome is still missing

Hallermann-Streiff syndrome is a rare congenital syndrome that is well-known but whose genetic cause has so far not been unraveled – although researchers have intensively investigated the disorder, using the latest applications of high-throughput sequencing, which have considerably facilitated the identification of disease-associated genes in recent years. Clinically, it presents as a combination of craniofacial dysmorphism, eye malformations, hair and skin anomalies, short stature, and, especially, a characteristic face that usually leads to the clinical diagnosis. Interestingly, affected children may also show signs of accelerated aging. Hallermann-Streiff syndrome thus belongs to the group of so called progeroid syndromes. In a review article published in the American Journal of Medical Genetics, researchers of the Institute of Human Genetics Göttingen summarize the current knowledge on the clinical characteristics of the syndrome and discuss the missing molecular link. Furthermore, they present innovative strategies that may be applied to identify the genetic basis of Hallermann-Streiff syndrome in the future.

Hallermann-Streiff syndrome: A missing molecular link for a highly recognizable syndrome.
Schmidt J, Wollnik B.
Am J Med Genet C Semin Med Genet. 2018 Dec;178(4):398-406. doi: 10.1002/ajmg.c.31668. Review.

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