Nemaline Myopathy
Our aims are to identify the genetic causes of the nemaline myopathies (NM) and related disorders, elucidate the pathogenetic mechanisms, develop diagnostic methods, and work towards therapeutic trials. One focus is on the nebulin gene. We have established mutational and clinical databases on NM.
Our research has focused on nemaline myopathy (NM) and related disorders. Our longstanding work in clinical research includes defining clinical and histological pictures of different subgroups of NM and related disorders. In molecular genetic research, the achievements of our group include the identification of two of the NM genes (NEB and TPM2), and some 300 pathogenic variants in more than 200 NM families. In addition, our group found the first TPM2 variants causing cap myopathy, the first NEB variants causing core-rod myopathy and the first NEB variants underlying distal myopathies not previously defined.
To enable the efficient detection of different types of variants in muscle genes, often difficult to analyse because of their size and structure, we have optimised a set of diagnostic methods such as custom-made microarrays and a nanopore sequencing technology. With these methods, novel types of disease-causing variants have been identified, illustrating the complexity of the genetics of the congenital myopathies.
The aim is to understand how these variants disrupt the function of the protein encoded, and how the faulty protein disrupts the functioning of the muscle tissue, leading to muscle weakness. To be able to offer interpretations, we have extended our methodology to include functional studies and work on cellular models. In addition, in collaboration with Dr. Kristen Nowak and Prof. Nigel G. Laing, our group has developed a nebulin mouse model.
The knowledge achieved through this work is crucial for understanding the pathogenetic mechanisms of NM and related disorders, which in turn is a prerequisite for developing therapies.
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Senior scientists :
Vilma-Lotta Lehtokari, PhD
Kirsi Kiiski, PhD
Affiliated senior scientist :
Docent Mikaela Grönholm, PhD
Postdoctoral fellow :
Jenni Laitila, PhD
Graduate students:
Lydia Sagath, MSc
Johanna Lehtonen, MSc
Staff:
Marilotta Turunen, Research Assistant
Fanny Rostedt, BSc, Research Assistant
Sagath L, Lehtokari VL, Välipakka S, Vihola A, Gardberg M, Hackman P, Pelin K, Jokela M, Kiiski K, Udd B, Wallgren-Pettersson C. Congenital asymmetric distal myopathy with hemifacial weakness caused by a heterozygous large de novo mosaic deletion in nebulin. Neuromuscul Disord. 2021 Jun;31(6):539-545.
Laitila J, McNamara EL, Wingate CD, Goullee H, Ross JA, Taylor RL, van der Pijl R, Griffiths L, Harries R, Ravenscroft G, Clayton JS, Sewry C, Lawlor MW, Ottenheijm CAC, Bakker AJ, Ochala J, Laing NG, Wallgren-Pettersson C, Pelin K, Nowak KJ: Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb. Acta Neuropathol Commun. 2020;8(1):18.
Laitila J, Lehtonen J, Lehtokari VL, Sagath L, Wallgren-Pettersson C, Grönholm M, Pelin K: A nebulin super-repeat panel reveals stronger actin binding toward the ends of the super-repeat region. Muscle Nerve. 2019;59(1):116-121.
Clarke AJ, Wallgren-Pettersson C: Ethics in genetic counselling. J Community Genet. 2019;10(1):3-33.
Kiiski K*, Lehtokari VL*, Vihola A, Laitila J, Huovinen S, Sagath L, Evilä A, Paetau A, Sewry C, Hackman P, Pelin K, Wallgren-Pettersson C, Udd B: Dominantly inherited distal nemaline/cap myopathy caused by a large deletion in the nebulin gene. NMD. 2019;29(2):97-107.
Kiiski K, Lehtokari VL, Löytynoja A, Ahlstén L, Laitila J, Wallgren-Pettersson C, Pelin K: A recurrent copy number variation of the NEB triplicate region: only revealed by the targeted nemaline myopathy CGH array. Eur J Hum Genet. 2016;24(4):574-580.
Lehtokari V-L, Kiiski K, Sandaradura SA, Laporte J, Repo P, Frey JA, Donner K, Marttila M, Saunders C, Barth PG, den Dunnen JT, Beggs A, Clarke NF, North KN, Laing, NG, Romero NB, Winder TL, Pelin K, Wallgren-Pettersson C: Mutation update: the spectrum of nebulin variants and associated myopathies. Human Mutat. 2014;35:1418-1426.
Marttila M*, Hanif M*, Lemola E, Nowak KJ, Laitila J, Grönholm M, Wallgren-Pettersson C, Pelin K: Nebulin interactions with actin and tropomyosin are altered by disease-causing mutations. Skelet Muscle. 2014;4:15.
Kiiski K, Laari L, Lehtokari V-L, Lunkka-Hytönen M, Angelini C, Petty R, Hackman P, Wallgren-Pettersson C, Pelin K: Targeted array CGH - a new diagnostic tool for the detection of large copy number variations in nemaline myopathy-causing genes. Neuromuscul. Disord. 2013;23:56-65.
Laitila J*, Hanif M*, Paetau A, Hujanen S, Keto J, Somervuo P, Huovinen S, Udd B, Wallgren-Pettersson C, Auvinen P, Hackman P, Pelin K: Expression of multiple nebulin isoforms in human brain. Muscle & Nerve. 2012;46:730-737.
Lehtokari VL, Pelin K, Herczegfalvi A, Karcagi V, Pouget J, Franques J, Pellissier JF, Figarella-Branger D, von der Hagen M, Huebner A, Schoser B, Lochmüller H, Wallgren-Pettersson C. Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy. Neuromuscul. Disord. 2011;21:556-562.
Lehtokari V-L*, Greenleaf RS*, DeChene ET, Kellinsalmi M, Pelin K, Laing NG, Beggs AH, Wallgren-Pettersson C: The exon 55 deletion in the nebulin gene - one single founder mutation with world-wide occurrence. Neuromuscul. Disord. 2009;19:179-181.
Romero NB*, Lehtokari VL*, Quijano-Roy S, Monnier N, Claeys KG, Carlier RY, Pellegrini N, Orlikowski D, Barois A, Laing NG, Lunardi J, Fardeau M, Pelin K, Wallgren-Pettersson C. Core-rod myopathy caused by mutations in the nebulin gene. Neurology. 2009;73(14):1159-61.
Wallgren-Pettersson C, Lehtokari V-L, Kalimo H, Paetau A, Hackman P, Sewry C, Pelin K, Udd B: Distal myopathy caused by homozygous missense mutations in the nebulin gene. Brain 2007;130:1465-1476.
Lehtokari VL, Ceuterick-de Groote C, de Jonghe P, Marttila M, Laing NG, Pelin K, Wallgren-Pettersson C: Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2. Neuromuscul Disord. 2007;17:433-442.
Donner K, Sandbacka M, Lehtokari V-L, Wallgren-Pettersson C, Pelin K: Complete genomic structure of the human nebulin gene and identification of alternatively spliced isoforms. Eur. J. Hum. Genet. 2004;12:744-51.
Donner K, Ollikainen M, Ridanpää M, Christen H-J, Goebel HH, de Visser M, Pelin K, Wallgren Pettersson C: Mutations in the β-tropomyosin (TPM2) gene - a rare cause of nemaline myopathy. Neuromuscul. Disord. 2002;12:151-158.
Pelin K, Hilpelä P, Sewry C , Akkari PA, Wilton SD, Wattanasirichaigoon D, Bang M-L, Centner T, Hanefeld F, Odent S, Fardeau M, Urtizberea JA, Muntoni F, Dubowitz V, Beggs AH, Laing NG, Labeit S, de la Chapelle A, Wallgren-Pettersson C. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc. Natl. Acad. Sci. USA 1999;96:2305-2310
Wallgren-Pettersson C, Pelin K, Hilpelä, Donner K, Porfirio B, Graziano C, Swoboda KJ, Fardeau M, Urtizberea JA, Muntoni F, Sewry C, Dubowitz V, Iannaccone S, Minetti C, Pedemonte M, Seri M, Cusano R, Lammens M, Castagna-Sloane A, Beggs AH, Laing NG, de la Chapelle A: Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy. Neuromuscul Disord. 1999;9:564-572.
The Folkhälsan Research Foundation
The Finska Läkaresällskapet (Medical Society of Finland)
The Magnus Ehrnrooth Foundation
The Medicinska Understödsföreningen Liv och Hälsa (Life and Health Medical Fund)
The Oskar Öflund Foundation
The Otto Malm Foundation
The University of Helsinki
A Foundation Building Strength for Nemaline Myopathy
Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkléns minne
Svenska kulturfonden
Waldemar von Frenckells stiftelse
The Distal Myopathy Group of Prof. Bjarne Udd, University Hospital of Tampere, Finland.
Stephan Lange Research laboratory, UC San Diego, California, USA
Prof. Nigel Laing and Dr. Kristen Nowak, Harry Perkins Institute, Perth, Australia
Associate prof. Julien Ochala, University of Copenhagen
Prof. Janna Saarela, Institute for Molecular Medicine Finland, Helsinki, and Centre for Molecular Medicine Norway, Oslo
The International Consortium on Nemaline Myopathy
Sinikka Hiekkala, the Finnish Association of Disabled People/Invalidiliitto ry
