Group UddNeuromuscular Disorders
The objective is to clarify the molecular pathology of known and not yet described human inherited neuromuscular disorders. After gene identification we continue with functional analyses. The identification of the underlying cause may eventually lead to prevention and treatment of the disorders.
Our achievements include primary identification of the genes underlying various neuromuscular disorders. These include tibial muscular dystrophy (TMD/LGMD2J, Udd myopathy), HMERF and other titinopathies caused by mutations in the TTN gene coding for the giant muscle protein titin (TTN). We also identified the causative TIA1 mutation in Welander distal myopathy. The research group has published genetic causes of especially distal myopathies, such as mutations in the J-domain of DNAJB6, CHCHD10, HSPB8 with a phenotype of distal myopathy and motor neuropathy, an X-linked myopathy SMPX and others. The titinopathies, are one of the cornerstones of research with several newly published findings through extensive international collaborations. Among others, we have published new splice variants that are associated with the recessively inherited muscle disease arthrogryposis multiplex congenita. The group has further developed criteria for the classification of TTN variants in myopathies. We have also further investigated the use of methods to sequence individual long RNA molecules to detect new splice variants in TTN. New analytical methods for detecting so-called CNV (copy number variations) mutations have been further developed and published. Our capacity to analyze the huge TTN on genomic, transcript and protein level is requested by research groups and clinicians around the world. We are conducting functional studies with the aim of understanding why some muscles are selectively affected in the disorders. The knowledge generated have led to accurate diagnostics, and may be used for therapeutic possibilities in the future.
Per Harald Jonson, PhD
Jaakko Sarparanta, PhD
Marco Savarese, PhD
Anna Vihola, PhD
Meharji Arumilli, MSc (part time)
Mridul Johari, MSc
Linda Forss (BSc)
Anna Vainio (BSc)
Helena Luque, BSc, Research Assistant
Merja Soininen, Laboratory Assistant
Hackman P., Vihola A., Haravuori H., Marchand S., Saraparanta J., de Seze J., Peltonen L., Richard I. and Udd B. Tibial muscular dystrophy (TMD) is a titinopathy - caused by mutations in TTN, the gene encoding the giant skeletal muscle protein titin. Am J Hum Genet 2002. 71:492-500.
Lange S., Xiang F., Yakovenko A,, Vihola A., Hackman P., Rostkova E., Kristensen J., Brandmeier B., Franzen G., Hedberg B., Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edström L, Ehler E, Udd B, Gautel M. (2005). The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover. Science 2005, 10;308(5728):1599-603.
Hackman P, Marchand S, Sarparanta J, Vihola A, Pénisson-Besnier I, Eymard B, Pardal-Fernández JM, Hammouda EH, Richard I, Illa I, and Udd B. Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscular Disorders 2008 18(12):922-8.
Raheem O, Olufemi S, Bachinski L, Vihola A, Sirito M, Holmlund-Hampf J, Haapasalo H, Li Y, Udd B and Krahe R. Mutant (CCTG)n expansion causes abnormal expression of ZNF9 in myotonic dystrophy type 2 (DM2). Am J Pathol 2010; 177:3025-36.
Sarparanta J, Jonson PH, Golzio C, Sandell S, Luque H, Screen M, McDonald K, Stajich JM, Mahjneh I, Vihola A, Raheem O, Penttilä S, Lehtinen S, Huovinen S, Palmio J, Tasca G, Ricci E, Hackman P, Hauser M, Katsanis N, Udd B. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet. 2012 44(4):450-5.
Hackman, P., Sarparanta, J., Lehtinen, S., Vihola, A., Evilä, A., Jonson, H., Luque H., Kere, J., Screen, M., Chinnery, P.F., Åhlberg, G., Edström, L., Udd, B. Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1. Annals of Neurology 2013. 73, 4, p. 500-509
Evilä A, Vihola A, Sarparanta J, Raheem O, Palmio J, Sandell S, Eymard B, Illa I, Rojas-Garcia R, Hankiewicz K, Negrão L, Löppönen T, Nokelainen P, Kärppä M, Penttilä S, Screen M, Suominen T, Richard I, Hackman P, Udd B. Atypical phenotypes in titinopathies explained by second titin mutations. Ann Neurol. 2014 75(2):230-40.
Charton K, Sarparanta J, Vihola A, Milic A, Jonson PH, Suel L, Luque H, Boumela I, Richard I, Udd B. CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy. Hum Mol Genet. 2015 Jul 1;24(13):3718-31
Huovinen S, Penttilä S, Somervuo P, Keto J, Auvinen P, Vihola A, Huovinen S, Pelin K, Raheem O, Salenius J, Suominen T, Hackman P, Udd B. Differential Isoform Expression and Selective Muscle Involvement in Muscular Dystrophies. Am J Pathol. 2015 Oct;185(10):2833-42.
Evilä A, Arumilli M, Udd B, Hackman P. Targeted next-generation sequencing assay for detection of mutations in primary myopathies. Neuromuscul Disord. 2016 Jan;26(1):7-15
Folkhälsan Research Foundation
Association Française contre les Myopathies (AFM)
Finska Läkaresällskapet (“Medical Society of Finland”)
Medicinska Understödsföreningen Liv och Hälsa (“Life and Health Medical Fund”)
Sigrid Jusélius Foundation
Academy of Finland
VTR( EVO) Governmental Grants
Magnus Ehrnrooth Foundation
Jane and Aatos Erkko Foundation
The Neuromuscular diagnostic Unit at Tampere University Hospital (TAYS): Johanna Palmio MD PhD, Sini Penttilä MSc, Tiina Suominen, PhD, Sara Lehtinen, MSc, Sanna Huovinen MD
dr. Isabelle Richard, Généthon, Evry, France
prof. Ana Ferreiro, Paris, France
prof. Mathias Gautel Kings College London, England,
doc. Carina Wallgren-Pettersson, Folkhälsan Research Center
doc. Katarina Pelin, Faculty of bioscience, University of Helsinki
prof. Ralf Krahe, Univ. of Texas, Houston, USA;
prof. Nigel Laing, Univ. of Western Australia, Perth, Australia
MD Giorgio Tasca, Catholic University of Rome, Italy
doc. Petri Auvinen, Institute of Biotechnology, University of Helsinki