Neuromuscular and Skeletal Diseases Working Group

Key research areas

The Neuromuscular and Skeletal Diseases working group, led by Univ.-Prof. Brunhilde Wirth, PhD, has been working since 1990 on the elucidation of genetic and pathomechanical causes of neuromuscular diseases, in particular spinal muscular atrophies (SMA) and diseases of the second motor neuron in the spinal cord. Recently, the group has also focused on osteoporosis and bone development. We are using state-of-the-art methods of exome and genome sequencing, transcriptome analysis, genome editing and induced pluripotent cells to identify genetic causes. Over the years, our laboratory has built up a wide range of methods to understand biochemical, cellular and pathological changes in motor neuron diseases and osteoporosis. We develop conditional and transgenic mouse models, zebra fish models and, more recently, Drosophila models for detailed analyses. Ultimately, this knowledge will contribute to the development of therapies, which is a particular focus of the laboratory.

A. Molecular genetics and biology of spinal muscular atrophy - elucidating the pathogenesis and searching for therapy

  • Search for SMA-modifying factors
  • Molecular biology and functional investigations of the survival motor neuron (SMN) genes and SMN interacting proteins to reveal cellular malfunctions of SMA
  • Investigating alternative splicing of SMN2
  • Developing a therapeutic approach for SMA patients based on activation of the SMN2 gene and the influencing SMA-modifying factors

B. Identifying new causal genes and functional characterization of unexplained motor neuron diseases

  • Recruiting families and patients with motor neuron diseases
  • Excluding 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: Revealing molecular causes of osteoporosis in PLS3 loss

  • Analysing the function of PLS3 in the development of bones in transgenic mice that overexpress PLS3
  • Analysing the impact of PLS3 overexpression on other bone diseases
  • Analysing PLS3 loss in conditional knockout mice
  • Clarifying the underlying pathological mechanism of osteoporosis due to PLS3 loss

Further information

External funding
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 NKröber 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


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

Curriculum Vitae
Academic career
2015 European Clinical Laboratory Geneticist
1996 Specialisation in human genetics at the Institute of Human Genetics, University of Bonn
1996 Post-doctoral professorship and research qualification at the Institute for Human Genetics at the University of Bonn (Prof Propping)
1989 Dissertation (PhD/Dr. rer. nat.) at the University of Bonn (Prof A. Gal)
1982 Master’s thesis in the Department for Cell Biology at the Faculty of Biology at the University of Bucharest, Romania (Prof Ionescu-Varo)
1982–1983 Specialisation in “applied genetics” at the Pasteur Institute of the University of Bucharest (Prof. Lungenau)
1978–1982 Biology degree at the University of Bucharest, Romania
Scientific and clinical history
Since 2003 Professor (C4) and Director of the Institute of Human Genetics at the University of Cologne, Head of the “Neuromuscular and Skeletal Diseases” working group
1996–2003 Senior research assistant (C2) at the Institute of Human Genetics at the University of Bonn, group leader
1990–1996 Research assistant (C1) at the Institute of Human Genetics at the University of Bonn, group leader
1989–1990 DFG post-doctoral student at the Imperial Cancer Research Fund Laboratorien in London (Prof Frischauf)
1986–1989 Doctoral student at the Institute of Human Genetics at the Medical University of Bonn (Prof Gal)
1983–1985 Biology teacher in Turnu Rosu, Romania
Awards and distinctions
2019 NRW Innovation Award
2001 1st Place Research Award “Motor-neuron Diseases” (Aventis, DGM)
1996 Sanofi-Wintrop Myopathy Award (DGM)
Memberships and service
Seit 2016 Chair of the Scientific Review Board of SMA Europe
Seit 2016 Chair of the Max-Delbrück Future Award at the University of Cologne
2010–2013 Chair of the Review Board of the CMMC (Center for Molecular Medicine Cologne)
Seit 2009 Member of the Scientific Review Board of the CMMC
2009–2016 Member of the Scientific Committee of the International Congress of Human Genetics
2009–2016 Chair of the Scientific Committee of the European Society of Human Genetics
Seit 2008 Co-director of the European School of Medical Genetics
2003–2017 Member of the Scientific Committee of the European Society of Human Genetics
2002–2006 Vice President of the German Society for Human Medicine
> 200 publications (H factor: 64, >16,000 citations according to Google Scholar: as of 01/06/2021


Dr. rer. nat. Uwe Becker, personal assistant
Andrea Delle Vedove, physician, MD-PhD candidate
Nur Cengiz, M.Sc., PhD candidate
Irmgard Hölker, medical-technical assistant
Dr. Mert Karakaya, clinical scientist, resident physician
Ilka Maus, M.Sc., PhD candidate
Jacqueline Lenz, cand med, MD candidate
Britta Meiger, animal keeper
Anixa Muinos-Bühl, M.Sc., PhD candidate
Roman Rombo, B.Sc., biological-technical assistant
Tamas Schmidt, M.Sc., PhD candidate
Jorge Soriano Campos, M.Sc., PhD candidate
Eike Strathmann, M.Sc., PhD candidate
Sofia Vrettou, M.Sc., PhD candidate
Lisa Wolff, M.Sc., PhD candidate
Sebastian Zetzsche, biological-technical assistant
Eleonora Zilio, M.Sc., PhD candidate

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