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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Research Article

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 1

LMOD3 mutations in patients with LMOD3-NM.

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LMOD3 mutations in patients with LMOD3-NM. Schematic of LMOD3 (NP_938012...
Schematic of LMOD3 (NP_938012) showing domain organization, with mutation positions indicated. Protein structure information was obtained from Chereau et al. (10), UniProt (http://www.uniprot.org/), and InterProScan 4 (37). LMOD3 contains 3 actin-binding domains (red) (actin-binding helix [A-h], residues 69–79; leucine-rich repeat domain [LLR], residues 237–402; Wiskott-Aldrich-syndrome protein homology 2 domain [WH2], residues 534–553) and 1 TM-binding helix (TM-h, residues 29–40). The functions of the proline-rich region (PolyP, residues 449–457), Glu-rich region (residues 86–179), and basic region (B, residues 489–498) are unknown. Mutations indicated in red font are associated with expression of mutant protein in Western blot studies (see Figure 2).