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, docent, PhD
Kirsi Kiiski, docent, PhD
Affiliated senior scientists
Mikaela Grönholm, Docent, PhD
Manu Jokela, Docent, MD, PhD, neurologist
Post-doctoral researcher
Jenni Laitila, PhD
Graduate students
Milla Laarne, MSc
Fanny Rostedt, MSc
Johanna Lehtonen, MSc
Staff
Marilotta Turunen, Laboratory Nurse
Teemu Turku, BSc, Research Assistant
Lehtonen J, Sulonen AM, Almusa H, Lehtokari VL, Johari M, Palva A, Hakonen AH, Wartiovaara K, Lehesjoki AE, Udd B, Wallgren-Pettersson C, Pelin K, Savarese M, Saarela J.
Haplotype information of large neuromuscular disease genes provided by linked-read sequencing has a potential to increase diagnostic yield.
Sci Rep. 2024 Feb 21;14(1):4306. doi: 10.1038/s41598-024-54866-4. PMID: 38383731; PMCID: PMC10881483.
Wallgren-Pettersson C, Jokela M, Lehtokari VL, Tyynismaa H, Sainio MT, Ylikallio E, Tynninen O, Pelin K, Auranen M.
Variants in tropomyosins TPM2 and TPM3 causing muscle hypertonia.
Neuromuscul Disord. 2024 Feb;35:29-32. doi: 10.1016/j.nmd.2023.12.006. Epub 2023 Dec 15. PMID: 38219297.
Lehtokari VL, Sagath L, Davis M, Ho D, Kiiski K, Kettunen K, Demczko M, Stein R, Vatta M, Winder TL, Shohet A, Orenstein N, Krcho P, Bohuš P, Huovinen S, Udd B, Pelin K, Laing NG, Wallgren-Pettersson C.
A recurrent ACTA1 amino acid change in mosaic form causes milder asymmetric myopathy.
Neuromuscul Disord. 2024 Jan;34:32-40. doi: 10.1016/j.nmd.2023.11.009. Epub 2023 Nov 30. PMID: 38142473.
Pelin K, Sagath L, Lehtonen J, Kiiski K, Tynninen O, Paetau A, Johari M, Savarese M, Wallgren-Pettersson C, Lehtokari VL.
Novel Compound Heterozygous Splice-Site Variants in TPM3 Revealed by RNA Sequencing in a Patient with an Unusual Form of Nemaline Myopathy: A Case Report.
J Neuromuscul Dis. 2023;10(5):977-984. doi: 10.3233/JND-230026. PMID: 37393515; PMCID: PMC10578209.
Lehtokari VL, Similä M, Tammepuu M, Wallgren-Pettersson C, Strang-Karlsson S, Hiekkala S.
Self-reported functioning among patients with ultra-rare nemaline myopathy or a related disorder in Finland: a pilot study.
Orphanet J Rare Dis. 2023 Nov 30;18(1):374. doi: 10.1186/s13023-023-02973-2. PMID: 38037113; PMCID: PMC10691147.
Sagath L, Lehtokari VL, Wallgren-Pettersson C, Pelin K, Kiiski K.
A custom ddPCR method for the detection of copy number variations in the nebulin triplicate region.
PLoS One. 2022 May 16;17(5):e0267793. doi: 10.1371/journal.pone.0267793. PMID: 35576196; PMCID: PMC9109913.
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.
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.
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.
Neuromuscular Disorders (Group Udd), The Folkhälsan Research Center
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
The Folkhälsan Research Foundation
The Finska Läkaresällskapet (Medical Society of Finland)
The Medicinska Understödsföreningen Liv och Hälsa (Life and Health Medical Fund)
Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkléns minne
Jane and Aatos Erkko Foundation
