Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy
Michaela Yuen, … , Kathryn N. North, Nigel F. Clarke
Michaela Yuen, … , Kathryn N. North, Nigel F. Clarke
Published September 24, 2014
Citation Information: J Clin Invest. 2014;124(11):4693-4708. https://doi.org/10.1172/JCI75199.
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Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

Abstract

Nemaline myopathy (NM) is a genetic muscle disorder characterized by muscle dysfunction and electron-dense protein accumulations (nemaline bodies) in myofibers. Pathogenic mutations have been described in 9 genes to date, but the genetic basis remains unknown in many cases. Here, using an approach that combined whole-exome sequencing (WES) and Sanger sequencing, we identified homozygous or compound heterozygous variants in LMOD3 in 21 patients from 14 families with severe, usually lethal, NM. LMOD3 encodes leiomodin-3 (LMOD3), a 65-kDa protein expressed in skeletal and cardiac muscle. LMOD3 was expressed from early stages of muscle differentiation; localized to actin thin filaments, with enrichment near the pointed ends; and had strong actin filament-nucleating activity. Loss of LMOD3 in patient muscle resulted in shortening and disorganization of thin filaments. Knockdown of lmod3 in zebrafish replicated NM-associated functional and pathological phenotypes. Together, these findings indicate that mutations in the gene encoding LMOD3 underlie congenital myopathy and demonstrate that LMOD3 is essential for the organization of sarcomeric thin filaments in skeletal muscle.

Authors

Michaela Yuen, Sarah A. Sandaradura, James J. Dowling, Alla S. Kostyukova, Natalia Moroz, Kate G. Quinlan, Vilma-Lotta Lehtokari, Gianina Ravenscroft, Emily J. Todd, Ozge Ceyhan-Birsoy, David S. Gokhin, Jérome Maluenda, Monkol Lek, Flora Nolent, Christopher T. Pappas, Stefanie M. Novak, Adele D’Amico, Edoardo Malfatti, Brett P. Thomas, Stacey B. Gabriel, Namrata Gupta, Mark J. Daly, Biljana Ilkovski, Peter J. Houweling, Ann E. Davidson, Lindsay C. Swanson, Catherine A. Brownstein, Vandana A. Gupta, Livija Medne, Patrick Shannon, Nicole Martin, David P. Bick, Anders Flisberg, Eva Holmberg, Peter Van den Bergh, Pablo Lapunzina, Leigh B. Waddell, Darcée D. Sloboda, Enrico Bertini, David Chitayat, William R. Telfer, Annie Laquerrière, Carol C. Gregorio, Coen A.C. Ottenheijm, Carsten G. Bönnemann, Katarina Pelin, Alan H. Beggs, Yukiko K. Hayashi, Norma B. Romero, Nigel G. Laing, Ichizo Nishino, Carina Wallgren-Pettersson, Judith Melki, Velia M. Fowler, Daniel G. MacArthur, Kathryn N. North, Nigel F. Clarke

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Figure 3

Clinical and histological features in NM due to LMOD3 mutations.

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Clinical and histological features in NM due to LMOD3 mutations. (A and ...
(A and B) Photographs of patients with LMOD3-NM. (A) Most affected individuals had severe generalized muscle weakness and hypotonia at birth and died in infancy (patient 9, severe congenital NM). (B) Patient 14a has less severe weakness and has survived into childhood. Note the severe facial and jaw weakness. (C) Control Gomori trichrome image (5-month-old child). (D and E) Skeletal muscle biopsy findings in (D) patient 6 and (E) patient 4. (D) Some biopsies had only a few scattered atrophic myofibers within abundant connective tissue. Nemaline bodies appear as purple or blue inclusions (arrow). (F) Control EM image (6-week-old child, rectus abdominis muscle). (G and H) EM images from some patient biopsies show myofibers with ordered sarcomeres adjacent to myofibers with disordered sarcomeres and thickened Z-discs. (I and J) Many nemaline bodies appear as thickened Z-discs, (I) sometimes in pairs interconnected by thin filaments. Some nemaline bodies resemble thickened Z-discs surrounded by a short thin filament “fringe.” Images show (G and J) patient 12a, (H) patient 14a, and (I) patient 1a. Scale bar: 50 μm (C–E); 2 μm (F–H); 500 nm (I and J).