Dominant Mutations in KBTBD13, a Member of the BTB/Kelch Family, Cause Nemaline Myopathy with Cores

• Published in: American journal of human genetics Vol. 87; no. 6; pp. 842 - 847
• Main Authors: Sambuughin, Nyamkhishig, Yau, Kyle S., Olivé, Montse, Duff, Rachael M., Bayarsaikhan, Munkhuu, Lu, Shajia, Gonzalez-Mera, Laura, Sivadorai, Padma, Nowak, Kristen J., Ravenscroft, Gianina, Mastaglia, Frank L., North, Kathryn N., Ilkovski, Biljana, Kremer, Hannie, Lammens, Martin, van Engelen, Baziel G.M., Fabian, Vicki, Lamont, Phillipa, Davis, Mark R., Laing, Nigel G., Goldfarb, Lev G.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 10.12.2010; Cell Press; Elsevier
• Subjects: Age of Onset; Amino Acid Sequence; Animals; Biological and medical sciences; Child; Chromosomes; Chromosomes, Human, Pair 15; Cytoskeleton; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes, Dominant; Genetics of eukaryotes. Biological and molecular evolution; Humans; Immunohistochemistry; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Muscle Proteins - genetics; Musculoskeletal system; Mutation; Mutation, Missense; Myopathies, Nemaline - genetics; Neuromuscular diseases; Proteins; Sequence Homology, Amino Acid; Studies; Human; Striated muscle disease; Family study; Nemaline myopathy; Genetics; Dominant character; Mutation; Congenital disease; Genetic disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2010.10.020

We identified a member of the BTB/Kelch protein family that is mutated in nemaline myopathy type 6 (NEM6), an autosomal-dominant neuromuscular disorder characterized by the presence of nemaline rods and core lesions in the skeletal myofibers. Analysis of affected families allowed narrowing of the candidate region on chromosome 15q22.31, and mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families. KBTBD13 contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. The identified disease-associated mutations, C.742C>A (p.Arg248Ser), c.1170G>C (p.Lys390Asn), and c.1222C>T (p.Arg408Cys), located in conserved domains of Kelch repeats, are predicted to disrupt the molecule's beta-propeller blades. Previously identified BTB/POZ/Kelch-domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of NEM6 are subjects for further studies.