Nemaline myopathy is a congenital muscle disorder that is characterized by the presence of rod-like structures (nemaline bodies) within myofibers. While multiple genes have been implicated in this disease, it is not clear how these gene products contribute to muscle dysfunction. Ankit Garg and colleagues at the University of Texas Southwestern Medical Center determined that mice lacking the muscle-specific protein KLHL40 develop a severe nemaline-like myopathy that is very similar to that observed in patients with a KLHL40-deficiency. KLHL40 localized to the thin filament proteins nebulin (NEB), which has been implicated in nemaline myopathy, and leiomodin 3 (LMOD3). The interaction of KLHL40 with NEB and LMOD3 functioned to stabilize these proteins and specifically prevented ubiquitination of LMOD3. Importantly, both LMOD3 and NEB were reduced in skeletal muscle from KLHL40-deficient animals as well as patients with KLHL40-depenedent nemaline mypopathy. The accompanying image shows a sagittal section of an embryonic day 15 mouse embryo that was probed for Klhl40 mRNA with an antisense radioisotopic probe. Klhl40 (pseudocolored red) only appears in developing muscle.
Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in
Ankit Garg, Jason O’Rourke, Chengzu Long, Jonathan Doering, Gianina Ravenscroft, Svetlana Bezprozvannaya, Benjamin R. Nelson, Nadine Beetz, Lin Li, She Chen, Nigel G. Laing, Robert W. Grange, Rhonda Bassel-Duby, Eric N. Olson