Institute of Human Genetics

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Neuromuscular and skeletal diseases working group

Main research areas

The Neuromuscular and Skeletal Diseases research group, headed by Prof. Dr. rer. nat. Brunhilde Wirth, has been investigating the genetic and pathomechanistic causes of neuromuscular diseases, in particular spinal muscular atrophies (SMA) and diseases of the 2nd motor neuron in the spinal cord, since 1990. Recently, the group has also focused on the elucidation of osteoporosis and bone development. We use the latest methods of exome and genome sequencing, transcriptome analysis, genome editing and induced pluripotent cells to identify genetic causes. For many years, the laboratory has developed a broad spectrum of methods to understand the biochemical, cellular and pathological changes in motor neuron diseases and osteoporosis. Conditional and transgenic mouse models, zebrafish and, more recently, Drosophilamodels are generated and analyzed in detail. Ultimately, all this knowledge leads to the development of therapies, which is a major focus of the laboratory.

A. Molecular genetics and biology of spinal muscular atrophy - elucidation of the pathogenesis and search for a therapy

  • Search for SMA-modifying genes
  • Molecular biological and functional investigation of survival motor neuron (SMN) genes and SMN-interacting proteins to uncover the cellular dysfunctions of SMA
  • Elucidation of the alternative splicing pathway of SMN2
  • Development of a therapeutic approach for SMA patients based on the activation of the SMN2 gene and manipulation of SMA modifying genes

B. Identification of novel causative genes and functional characterization of unexplained motor neuron diseases

  • Recruitment of families and patients with motor neuron diseases
  • Exclusion of known genes by sequencing all known genes on a motor neuron gene panel
  • Exome sequencing to identify underlying pathogenic variants
  • Functional analysis of potential pathogenic variants in cellular systems and model organisms

C. Osteoporosis: Uncovering the molecular causes of osteoporosis in PLS3 loss

  • Analysis of the function of PLS3 in bone development in transgenic mice overexpressing PLS3
  • Analysis of the impact of PLS3 overexpression on other bone diseases
  • Analysis of the loss of PLS3 in conditional knockout mice
  • Elucidation of the underlying pathomechanism of osteoporosis due to PLS3 loss

Further information

Third-party funds

Selected publications

Wirth B.
Spinal Muscular Atrophy: In the Challenge Lies a Solution.
Trends Neurosci. 2021 Apr;44(4):306-322
PubMed PMID: 33423791

Torres-Benito L., Schneider S., Rombo R., Ling K.K., Grysko V., Upadhyay A., Kononenko N.L., Rigo F., Bennett C.F. & Wirth B.
NCALD Antisense Oligonucleotide Therapy in Addition to Nusinersen further Ameliorates Spinal Muscular Atrophy in Mice.
Am J Hum Genet. 2019 Jul 3; 105(1):221-230
PubMed PMID: 31230718

Janzen E, Mendoza-Ferreira N, Hosseinibarkooie S, Schneider S, Hupperich K, Tschanz T, Grysko V, Riessland M, Hammerschmidt M, Rigo F, Bennett CF, Kye MJ, Torres-Benito L, Wirth B.
CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis.
Brain. 2018 Aug 1;141(8):2343-2361
PubMed PMID: 29961886

Riessland M*, Kaczmarek A*, Schneider S*, Swoboda KJ, Löhr H, Bradler C, Grysko V, Dimitriadi M, Hosseinibarkooie S, Torres-Benito L, Peters M, Upadhyay A, Biglari N, Kröber S, Hölker I, Garbes L, Gilissen C, Hoischen A, Nürnberg G, Nürnberg P, Walter M, Rigo F, Bennett CF, Kye MJ, Hart AC, Hammerschmidt M, Kloppenburg P, Wirth B.
Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis.
Am J Hum Genet. 2017;100(2):297-315.
PubMed PMID: 28132687

Hosseinibarkooie S*, Peters M*, Torres-Benito L, Rastetter RH, Hupperich K, Hoffmann A, Mendoza-Ferreira N, Kaczmarek A, Janzen E, Milbradt J, Lamkemeyer T, Rigo F, Bennett CF, Guschlbauer C, Büschges A, Hammerschmidt M, Riessland M, Kye MJ, Clemen CS, Wirth B.
The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype.
Am J Hum Genet. 2016 Sep 1;99(3):647-65.
PubMed PMID: 27499521

van Dijk FS, Zillikens MC, Micha D, Riessland M, Marcelis CL, de Die-Smulders CE, Milbradt J, Franken AA, Harsevoort AJ, Lichtenbelt KD, Pruijs HE, Rubio-Gozalbo ME, Zwertbroek R, Moutaouakil Y, Egthuijsen J, Hammerschmidt M, Bijman R, Semeins CM, Bakker AD, Everts V, Klein-Nulend J, Campos-Obando N, Hofman A, te Meerman GJ, Verkerk AJ, Uitterlinden AG, Maugeri A, Sistermans EA, Waisfisz Q, Meijers-Heijboer H, Wirth B, Simon ME, Pals G.

PLS3 mutations in X-linked osteoporosis with fractures.
N Engl J Med. 2013 Oct 17;369(16):1529-36. doi: 10.1056/NEJMoa1308223. Epub 2013 Oct 2.
PubMed PMID: 24088043

Oprea GE, Kröber S, McWhorter ML, Rossoll W, Müller S, Krawczak M, Bassell GJ, Beattie CE, Wirth B.
Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy.
Science. 2008;320(5875):524-7
PubMed PMID: 18440926

Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, Eyupoglu IY, Wirth B.
Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.
Hum Mol Genet, 2003;12:2481-9.
PubMed PMID: 12915451

Feldkötter M, Schwarzer V, Wirth R, Wienker TF, Wirth B.
Quantitative analysis of SMN1 and SMN2 based on real-time LightCycler PCR: Fast and highly reliable heterozygosity testing and prediction of severity of spinal muscular atrophy.
Am J Hum Genet, 2002, 70:358-368.
PubMed PMID: 11791208

Lorson CL*, Hahnen E*, Androphy EJ, Wirth B.
A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.
Proc Natl Acad Sci USA, 1999, 96 (11):6307-6311
PubMed PMID: 10339583

Patents

B. Wirth & M. Riessland, US 61/859,664, Neurocalcin Delta Inhibitors and Therapeutic and Non-Therapeutic Uses Thereof, Patent filed 29.07.2014, Patent issued in US & EU in 2018

B. Wirth, E. Janzen, N. Mendoza-Ferreira, SM Hosseinibarkooie, EP 17172826, Calcineurin B Homologous Protein 1 Inhibitors and Therapeutic and Non-Therapeutic Uses Thereof, Patent filed 24.05. 2017, PCT/EP2018/063562

Univ.-Prof.--Wirth-Brunhilde
Univ.-Prof. Brunhilde Wirth, PhD

Specialist in Human Genetics, GfH (German Society of Human Genetics)
European Clinical Laboratory Geneticist

Profile on Researchgate
Profile on CMMC

Publications (Google Scholar)

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Academic career
2015European Clinical Laboratory Geneticist
1996Specialisation in human genetics at the Institute of Human Genetics, University of Bonn
1996Post-doctoral professorship and research qualification at the Institute for Human Genetics at the University of Bonn (Prof Propping)
1989Dissertation (PhD/Dr. rer. nat.) at the University of Bonn (Prof A. Gal)
1982Master’s thesis in the Department for Cell Biology at the Faculty of Biology at the University of Bucharest, Romania (Prof Ionescu-Varo)
1982–1983Specialisation in “applied genetics” at the Pasteur Institute of the University of Bucharest (Prof. Lungenau)
1978–1982Biology degree at the University of Bucharest, Romania
Scientific and clinical history
Since 2003Professor (C4) and Director of the Institute of Human Genetics at the University of Cologne, Head of the “Neuromuscular and Skeletal Diseases” working group
1996–2003Senior research assistant (C2) at the Institute of Human Genetics at the University of Bonn, group leader
1990–1996Research assistant (C1) at the Institute of Human Genetics at the University of Bonn, group leader
1989–1990DFG post-doctoral student at the Imperial Cancer Research Fund Laboratorien in London (Prof Frischauf)
1986–1989Doctoral student at the Institute of Human Genetics at the Medical University of Bonn (Prof Gal)
1983–1985Biology teacher in Turnu Rosu, Romania
Awards and distinctions
2023Duchenne-Erb Prize (DGM)
2019NRW Innovation Award
20011st Place Research Award “Motor-neuron Diseases” (Aventis, DGM)
1996Sanofi-Wintrop Myopathy Award (DGM)
Memberships and service
Seit 2016Chair of the Scientific Review Board of SMA Europe
Seit 2016Chair of the Max-Delbrück Future Award at the University of Cologne
2010–2013Chair of the Review Board of the CMMC (Center for Molecular Medicine Cologne)
Seit 2009Member of the Scientific Review Board of the CMMC
2009–2016Member of the Scientific Committee of the International Congress of Human Genetics
2009–2016Chair of the Scientific Committee of the European Society of Human Genetics
Seit 2008Co-director of the European School of Medical Genetics
2003–2017Member of the Scientific Committee of the European Society of Human Genetics
2002–2006Vice President of the German Society for Human Medicine
Publications
> 225 publications (H factor: 69, >20,200 citations according to Google Scholar: as of 04.11.2023)
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The team

Dr. rer. nat. Uwe Becker, personal assistant
Nur Cengiz, M.Sc., doctoral student
Dr. Mert Karakaya, specialist in human genetics
Lidia Ryba-Fröhlich, dishwasher
Tamas Schmidt, M.Sc., doctoral student
Sofia Vrettou, M.Sc., doctoral student