Nemaline myopathy (NEM) is a rare congenital muscle disease that in severe cases results in neonatal death due to respiratory insufficiency. NEM is characterized clinically by skeletal muscle dysfunction (most frequently hypotonia and weakness) and the presence of electron-dense nemaline bodies (rods) on muscle biopsy (Romero et al., 2013). Mutations in eight known genes have previously been found to cause NEM, with six of these encoding thin filament or thin filament-associated proteins (skeletal muscle α-actin, cofilin-2, nebulin, α- and β-tropomyosins, and troponin T1) (Romero et al., 2013). Most recently, causative mutations in genes encoding BTB-Kelch proteins have been identified in myopathies associated with nemaline bodies (KBTBD13 in autosomal dominant core-rod disease (Sambuughin et al., 2010) and KLHL40 in autosomal recessive NEM (Ravenscroft et al., 2013)). We performed whole exome sequencing of genetically unresolved severe NEM patients and identified recessive small deletions and missense changes in a third gene encoding a skeletal muscle specific BTB-Kelch protein (Kelch-like family member 41; KLHL41) in four individuals from unrelated NEM families. Subsequent Sanger sequencing identified compound heterozygous changes in KLHL41 in a fifth NEM family. Functional studies in zebrafish showed that loss of klhl41 results in diminished motor function and myofibrillar disorganisation. KLHL40 (also known as sarcosin, Krp1 and KBTBD10) has previously been implicated in myofibril assembly (Greenberg et al., 2008; Paxton et al., 2011; du Puy et al., 2012). Studies of BTB-Kelch proteins, have indicated that members of this protein family (there are over 50 in humans) act as substrate adaptors for E3 ubiquitin ligases (Prag & Adams, 2003; Sambuughin et al., 2012). Despite these studies, the roles of BTB-Kelch proteins in skeletal muscle remain largely unknown. In conclusion, these studies expand the genetic heterogeneity of NEM, and further implicate a critical role of BTB-Kelch family members in maintenance of sarcomeric integrity.
du Puy L, et al. (2012). Sarcosin (Krp1) in skeletal muscle differentiation: gene expression profiling and knockdown experiments. Int J Dev Biol 56, 301-309.
Greenberg CC, et al. (2008). Krp1 (Sarcosin) promotes lateral fusion of myofibril assembly intermediates in cultured mouse cardiomyocytes. Exp Cell Res 314, 1177-1191.
Paxton CW, et al. (2011). BTB-Kelch protein Krp1 regulates proliferation and differentiation of myoblasts. Am J Physiol Cell Physiol 300, C1345-1355.
Prag S & Adams JC. (2003). Molecular phylogeny of the kelch-repeat superfamily reveals an expansion of BTB/kelch proteins in animals. BMC Bioinformatics 4, 42.
Ravenscroft G, et al. (2013). Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy. Am J Hum Genet 93, 6-18.
Romero NB, Sandaradura SA & Clarke NF. (2013). Recent advances in nemaline myopathy. Curr Opin Neurol 26, 519-526.
Sambuughin N, et al. (2012). KBTBD13 interacts with Cullin 3 to form a functional ubiquitin ligase. Biochem Biophys Res Commun 421, 743-749.
Sambuughin N, et al. (2010). Dominant Mutations in KBTBD13, a Member of the BTB/Kelch Family, Cause Nemaline Myopathy with Cores. Am J Hum Genet 87, 842-847.