AG Neuro(onco)genetics, Nephrogenetics
Head: Prof. Dr. med. Ruthild G. Weber
"We identify (new) disease-relevant genes in the germline of patients with brain tumors or other rare diseases of the brain or kidneys, as well as somatic aberrations in brain tumor genomes. We use genome-wide screening methods (microarray analyses and next generation sequencing for parallel sequencing of multiple genes or the entire exome or genome) followed by detailed data analysis with various analysis and filter strategies.
We also characterize selected genes or genetic variants in cell and animal models.
In order to be able to use the generated results in the Clinical Department (translation), we carry out projects on personalized genomic medicine in close cooperation with various medical disciplines within and outside the MHH."
Ruthild G. Weber(expert profile, e-mail)
Staff members
- Dr. rer. nat. Frank Brand, post-doc with a research focus on "Neurooncogenetics" and deputy research group leader
- Dr. med. Leonie Greipel, physician in further training as a specialist in pediatrics with a focus on nephrology and Clinician Scientist in the project "Genetic aberrations in kidney transplant patients with congenital anomalies of the kidneys and urinary tract: elucidation of the genetic cause and correlation with the outcome after transplantation" of the Clinician Scientist Program PRACTIS of the Hannover Medical School funded by the German Research Foundation (DFG)
- Carlotta Sophie Kornblum, B.Sc., Master's student in the Biomedicine program at the MHH with a Master's thesis on "Neurooncogenetics"
- Dr. rer. nat. Helge Martens, post-doc with a research focus on "Nephrogenetics"
- Lily Sophie Rose, M. Sc., PhD student in the MD/PhD program "Molecular Medicine" at the Hannover Biomedical Research School (HBRS) of the MHH
- Jessica Wolf-Klenner, B.Sc., laboratory intern, Master's program in Biomedicine at the MHH
Alumni
- Dr. med. Elena Basenach
- Dr. rer. nat. Ulrike Beyer
- Martin Bucher, M. Sc.
- Dr. rer. nat. Anne Christians née Kosfeld
- Dr. med. Natalie Elyan
- Dr. rer. nat. Alisa Förster
- Dr. med. Isabel Gogol
- Dr. rer. nat. Esra Kesdiren
- Dr. med. Alma Osmanovic
- Dr. med. Isolde Rangnau
- Dr. rer. nat. Vera Riehmer
- Sofie B. Trummer, M. Sc.
- Dr. rer. nat. Christine Weber
- Dr. med. Lina Werfel
- Dr. med. Maylin Widjaja
Our research objective
Our aim is to identify new disease-relevant genes that are altered in brain tumors or that underlie the development of brain tumors. We are also looking for new genes whose alterations cause other rare diseases of the brain or kidneys, e.g. amyotrophic lateral sclerosis or malformations of the kidneys and urinary tract (CAKUT).
In an interdisciplinary collaboration with pathologists and developmental biologists, identified candidate genes and genetic variants are characterized in cell and animal models in order to investigate their disease relevance. This should provide the basis for a more comprehensive understanding of the underlying clinical pictures in the respective patients.
Through close interdisciplinary feedback, e.g. with neurologists, neurosurgeons, pediatric nephrologists and pediatric urologists, work is being done to use the genetic data for more targeted and, if possible, preventive patient care.
Our main areas of research
Identification of brain tumour predisposition genes, functional characterization of selected variants and development/investigation of targeted therapeutic approaches
In most cases, gliomas do not occur in families. However, there are cancer predisposition syndromes in which gliomas are part of the tumor spectrum.
In this project, we are investigating whether we can find a genetic cause for the tumor disease in families with several glioma patients, in glioma patients with a positive tumor history in the family or in glioma patients with multiple tumors.
This project will be carried out in the following steps:
- Whole exome or genome sequencing in glioma families as well as patients with multiple tumors (including gliomas) or positive tumor history in the family using next generation sequencing (NGS) technologies. This is followed by detailed data analysis using various analysis and filtering strategies to identify likely causative genetic germline alterations.
- Verification of selected NGS variants using Sanger sequencing and co-segregation analyses in the families.
- Characterization of selected variants in cell and animal models to demonstrate their pathogenicity.
- Mutation analysis of selected candidate genes in larger collectives of glioma patients to investigate their significance for glioma pathogenesis.
- Sequencing of the entire exome or genome in familial gliomas using NGS technologies. This is followed by detailed data analysis using various analysis and filtering strategies to identify somatic aberrations.
Collaborations:
Prof. Dr. Christian Hartmann, Neuropathology, MHH; Prof. Dr. Joachim Krauss, Dr. Bujung Hong, Prof. Dr. Kerstin Schwab, Neurosurgery, MHH; Prof. Dr. Amir Samii, INI, Hannover; Prof. Dr. Fedor Heidenreich, Dr. Bettina Wiese, Neurology, DIAKOVERE Henriettenstiftung, Hanover; Dr. Stephan Wolf, NGS Core Facility, DKFZ Heidelberg; German Glioma Network (Coordinator: Prof. Dr. Michael Weller).
Funding:
Wilhelm Sander Foundation.
Selected publications:
Weber CAM, Krönke N, Volk V, Auber B, Förster A, Trost D, Geffers R, Esmaeilzadeh M, Lalk M, Nabavi A, Samii A, Krauss JK, Feuerhake F, Hartmann C, Wiese B, Brand F, Weber RG.
Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families.
Acta Neuropathol Commun, 11, 184, 2023[read online]
Basenach E, Förster A, Raab P, Alzein S, Schmidt G, Krauss JK, Schlegelberger B, Heidenreich F, Auber B, Hartmann C, Wiese B, Weber RG.
Sustained response to bevacizumab in a patient with mosaic neurofibromatosis type 2 carrying the NF2:c.784C>T p.(Arg262*) variant.
Clin Neuropathol, 41, 162-167, 2022.
Förster A, Brand F, Banan R, Hüneburg R, Weber CAM, Ewert W, Kronenberg J, Previti C, Elyan N, Beyer U, Martens H, Hong B, Bräsen JH, Erbersdobler A, Krauss JK, Stangel M, Samii A, Wolf S, Preller M, Aretz S, Wiese B, Hartmann C, Weber RG.
Rare germline variants in the E-cadherin gene CDH1 are associated with the risk of brain tumors of neuroepithelial and epithelial origin.
Acta Neuropathol, 142, 191-210, 2021[read online]
Beyer U, Brand F, Martens H, Weder J, Christians A, Elyan N, Hentschel B, Westphal M, Schackert G, Pietsch T, Hong B, Krauss JK, Samii A, Raab P, Das A, Dumitru CA, Sandalcioglu IE, Hakenberg OW, Erbersdobler A, Lehmann U, Reifenberger G, Weller M, Reijns MAM, Preller M, Wiese B, Hartmann C, Weber RG.
Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis.
Acta Neuropathol, 134, 905-922, 2017[read online]
Characterization of the novel tumor suppressor protein focadhesin
In the search for novel genes on 9p relevant to the pathogenesis of brain tumors, especially gliomas, we characterized a t(7;9) in a glioblastoma primary culture.
Based on these data, the Human Gene Nomenclature Committee proposed the name focadhesin and the gene symbol FOCAD. In vitro assays showed an influence of focadhesin on the proliferation and motility of glioblastoma cells.
Furthermore, in the murine xenograft model, we were able to show a significantly lower growth of glioblastoma cell lesions with focadhesin versus without focadhesin expression (Brockschmidt et al., Brain, 2012).
To further characterize focadhesin, interaction partners of KIAA1797/focadhesin are currently identified in the yeast two-hybrid screen, verified by co-immunoprecipitation, and the intracellular localization of the interactions is determined by immunofluorescence and functional in vitro analyses are performed.
Collaborations:
Prof. Dr. Peter Claus, Institute of Neuroanatomy, MHH; Carina Thomé, Prof. Dr. Wolfgang Wick, DKFZ Heidelberg; Dr. Marc-Steffen Raab, DKFZ Heidelberg.
Funding:
University internal performance funding HiLF.
Selected publications:
Brand F, Förster A, Christians A, Bucher M, Thomé CM, Raab MS, Westphal M, Pietsch T, von Deimling A, Reifenberger G, Claus P, Hentschel B, Weller M, Weber RG.
FOCAD loss impacts microtubule assembly, G2/M progression and patient survival in astrocytic gliomas.
Acta Neuropathol, 139, 175-192, 2020[read online]
Brockschmidt A, Trost D, Peterziel H, Zimmermann K, Ehrler M, Grassmann H, Pfenning P, Waha A, Wohlleber D, Brockschmidt FF, Jugold M, Hoischen A, Kalla C, Waha A, Seifert G, Knolle PA, Latz E, Hans VH, Wick W, Pfeifer A, Angel P, Weber RG. KIAA1797/FOCAD encodes a novel focal adhesion protein with tumor suppressor function in gliomas.
Brain, 135, 1027-1041, 2012.
Identification of genetic causes of amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disease that usually occurs sporadically. As there are also familial cases, it is suspected that genetic factors may be the cause. There are five known genes whose alteration is more frequently the basis of ALS.
In this project, new ALS candidate genes will be identified and selected variants in new ALS candidate genes will be characterized. In addition, the genetic findings will be translated into the Clinical Department to enable more targeted patient care.
This project will be carried out in the following steps:
- Sequencing of the whole exome or genome of ALS patients or ALS trios (i.e. ALS patients and their healthy parents) using NGS technologies followed by (a) identification of likely causative aberrations by candidate gene analysis or (b) identification of de novo aberrations by trio-based de novo analysis.
- Verification of selected NGS variants by Sanger sequencing.
- Mutation analysis of selected candidate genes in larger collectives of ALS patients to investigate their relevance for ALS pathogenesis.
- Characterization of selected variants in the cell model for pathogenicity detection.
- Reverse phenotyping of patients following genetic characterization for (a) verification of variant pathogenicity in vivo and (b) use of genetic findings for patient care.
Collaborations:
Prof. Dr. Susanne Petri, Clinical Department of Neurology, MHH; Dr. Peter Raab, Institute of Diagnostic and Interventional Radiology, MHH.
Funding:
Clinician Scientist Program PRACTIS of the MHH funded by the German Research Foundation DFG, KlinStrucMed Program of the MHH funded by the Else Kröner-Fresenius Foundation, University internal performance funding HiLF, Petermax Müller Foundation Hannover.
Selected publications:
Osmanovic A, Förster A, Widjaja M, Auber B, Das AM, Christians A, Brand F, Petri S, Weber RG.
A SUMO4 initiator codon variant in amyotrophic lateral sclerosis reduces SUMO4 expression and alters stress granule dynamics.
J Neurol, 269, 4863-4871, 2022[read online]
Osmanovic A, Gogol I, Martens H, Widjaja M, Müller K, Schreiber-Katz O, Feuerhake F, Langhans C-D, Schmidt G, Andersen PM, Ludolph AC, Weishaupt JH, Brand F, Petri S, Weber RG.
Heterozygous DHTKD1 variants in two European cohorts of amyotrophic lateral sclerosis patients.
Genes (Basel), 13, 84, 2022[read online].
Osmanovic A, Widjaja M, Förster A, Weder J, Wattjes MP, Lange I, Sarikidi A, Auber B, Raab P, Christians A, Preller M,
Petri S, Weber RG.
SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia.
J Neurol, 267, 2732-2743, 2020[read online]
Osmanovic A, Rangnau I, Kosfeld A, Abdulla S, Janssen C, Auber B, Raab P, Preller M, Petri S, Weber RG.
FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study.
Eur J Hum Genet, 25, 324-331, 2017[read online].
Identification of genetic causes of congenital anomalies of the kidneys and urinary tract (CAKUT) and functional characterization of selected genes or genetic variants in cell and animal models
The term CAKUT covers malformations of the kidneys and urinary tract, such as renal agenesis, renal hypodysplasia and hydro/megaureter. To date, around 30 genes are known whose mutations can cause CAKUT. Since a mutation analysis of the known genes in CAKUT patients is often unsuccessful, there are probably still a large number of undiscovered genes whose aberration can cause CAKUT.
In this project, new genetic CAKUT causes will be identified and selected variants in new CAKUT candidate genes will be characterized. Exome-wide examinations of DNA from peripheral blood of CAKUT patients will be used to clarify as many cases as possible. The genetic findings obtained in this way are to be translated into the Clinical Department for more targeted patient care.
This project will be carried out in the following steps:
- Sequencing of the entire exome or genome in CAKUT families as well as patients with isolated CAKUT using NGS technologies. This will be followed by detailed data analysis using different analysis and filtering strategies to identify likely causative genetic germline alterations.
- Verification of selected NGS variants using Sanger sequencing, co-segregation analysis in families, determination of the parental origin of inherited variants.
- Mutation analysis of selected candidate genes in larger collectives of CAKUT patients to investigate their significance for CAKUT pathogenesis.
- Characterization of selected variants / CAKUT candidate genes in cell and animal models.
- Detection of the expression of CAKUT candidate genes during murine kidney development at different developmental stages.
- Macroscopic and microscopic examination of mouse kidneys with a knockout of the identified CAKUT candidate genes.
- Immunohistochemical analysis of nephrectomy specimens from CAKUT patients.
Collaborations:
Prof. Dr. Dieter Haffner, Clinical Department of Paediatric Kidney, Liver and Metabolic Diseases, MHH; Prof. Dr. Benno Ure, PD Dr. Barbara Ludwikowski, Center for Pediatric Surgery Hannover; Prof. Dr. Martin Kirschstein, General Hospital Celle; Prof. Dr. Hans-Heinrich Kreipe, PD Dr. Jan Hinrich Bräsen, Institute of Pathology, MHH; Prof. Dr. Andreas Kispert, Institute of Molecular Biology, MHH; PD Dr. Christoph Daniel, Prof. Dr. Kerstin Amann, Nephropathology Department, University Hospital Erlangen; Dr. Anna Kristina Bjerre, Oslo Universitetssykehus, Oslo, Norway; Prof. Dr. Thomáš Seeman, Children's Clinic of Motol University Hospital, Charles University Prague, Czech Republic; Dr. Cécile Jeanpierre, Inserm U1163 Institute Imagine, Paris, France; Prof. Dr. Velibor Tasic, University Children's Hospital, Faculty of Medicine Skopje, North Macedonia.
Funding:
German Research Foundation DFG, TITUS Research College of the Hannover Medical School funded by the Else Kröner-Fresenius Foundation.
Selected publications:
Greipel L, Martens H, Werfel L, Gjerstad AC, Auber B, Geffers R, Bräsen JH, Jankauskiene A, Bjerre A, Kanzelmeyer N, Haffner D, Weber RG.
Presentation of Patients With Congenital Anomalies of the Kidney and Urinary Tract and PAX2 Loss-of-Function Variants and Implications for Clinical Management.
Kidney Int Rep, 2025 Sep 03 [Online ahead of print][read online]
Kesdiren E, Martens H, Brand F, Werfel L, Wedekind L, Trowe MO, Schmitz J, Hennies I, Geffers R, Gucev Z, Seeman T, Schmidt S, Tasic V, Fasano L, Bräsen JH, Kispert A, Christians A, Haffner D, Weber RG.
Heterozygous variants in the teashirt zinc finger homeobox 3 (TSHZ3) gene in human congenital anomalies of the kidney and urinary tract.
Eur J Hum Genet, 33, 44-55, 2025[read online].
Werfel L, Martens H, Hennies I, Gjerstad AC, Fröde K, Altarescu G, Banerjee S, Valenzuela Palafoll I, Geffers R, Kirschstein M, Christians A, Bjerre A, Haffner D, Weber RG.
Diagnostic yield and benefits of whole-exome sequencing in CAKUT patients diagnosed in the first thousand days of life.
Kidney Int Rep, 8, 2439-2457, 2023[read online].
Christians A, Kesdiren E, Hennies I, Hofmann A, Trowe M-O, Brand F, Martens H, Gjerstad AC, Gucev Z, Zirngibl M, Geffers R, Seeman T, Billing H, Bjerre A, Tasic V, Kispert A, Ure B, Haffner D, Dingemann J, Weber RG.
Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2.
Hum Genet, 142, 73-88, 2023.[read online]
Martens H, Hennies I, Getwan M, Christians A, Weiss A-C, Brand F, Gjerstad AC, Christians A, Gucev Z, Geffers R, Seeman T, Kispert A, Tasic V, Bjerre A, Lienkamp SS, Haffner D, Weber RG.
Rare heterozygous GDF6 variants in patients with renal anomalies.
Eur J Hum Genet, 28, 1681-1693, 2020[read online]
Christians A, Weiss AC, Martens H, Klopf MG, Hennies I, Haffner D, Kispert A, Weber RG.
Inflammation-like changes in the urothelium of Lifr-deficient mice and LIFR-haploinsufficient humans with urinary tract anomalies.
Hum Mol Genet, 29, 1192-1204, 2020[read online]
Kosfeld A, Martens H, Hennies I, Haffner D, Weber RG.
Congenital anomalies of the kidneys and urinary tract (CAKUT).
Med Gen, 30, 448-460, 2018[read online]
Kosfeld A, Brand F, Weiss AC, Kreuzer M, Goerk M, Martens H, Schubert S, Schäfer AK, Riehmer V, Hennies I, Bräsen JH, Pape L, Amann K, Krogvold L, Bjerre A, Daniel C, Kispert A, Haffner D, Weber RG.
Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations.
Hum Mol Genet, 26, 1716-1731, 2017.
Kosfeld A, Kreuzer M, Daniel C, Brand F, Schäfer AK, Chadt A, Weiss AC, Riehmer V, Jeanpierre C, Klintschar M, Bräsen JH, Amann K, Pape L, Kispert A, Al-Hasani H, Haffner D, Weber RG.
Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT).
Hum Genet, 135, 69-87, 2016[read online]
Classen CF, Riehmer V, Landwehr C, Kosfeld A, Heilmann S, Scholz C, Kabisch S, Engels H, Tierling S, Zivicnjak M, Schacherer F, Haffner D, Weber RG.
Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis.
Hum Genet, 132, 825-841, 2013[read online].
Brockschmidt A, Chung B, Weber S, Fischer D-C, Kolatsi-Joannou M, Christ L, Heimbach A, Shtiza D, Klaus G, Simonetti GD, Konrad M, Winyard P, Haffner D, Schaefer F, Weber RG.
CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT).
Nephrol Dial Transplant, 27, 2355-2364, 2012.
Weber S, Landwehr C, Renkert M, Hoischen A, Wühl E, Denecke J, Radlwimmer B, Haffner D, Schaefer F, Weber RG.
Mapping candidate regions and genes for congenital anomalies of the kidneys and urinary tract (CAKUT) by array-based comparative genomic hybridization.
Nephrol Dial Transplant, 26, 136-143, 2011.