Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores.
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.
Department of Anesthesiology, Uniformed Services University, Bethesda, MD 20814, USA. nsambuughin@usuhs.mil
Nyamkhishig
N
Sambuughin
Kyle S
KS
Yau
Montse
M
Olivé
Rachael M
RM
Duff
Munkhuu
M
Bayarsaikhan
Shajia
S
Lu
Laura
L
Gonzalez-Mera
Padma
P
Sivadorai
Kristen J
KJ
Nowak
Gianina
G
Ravenscroft
Frank L
FL
Mastaglia
Kathryn N
KN
North
Biljana
B
Ilkovski
Hannie
H
Kremer
Martin
M
Lammens
Baziel G M
BG
van Engelen
Vicki
V
Fabian
Phillipa
P
Lamont
Mark R
MR
Davis
Nigel G
NG
Laing
Lev G
LG
Goldfarb
D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002884:Chromosomes, Human, Pair 15; D005799:Genes, Dominant; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D017696:Myopathies, Nemaline / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
C555066:KBTBD13 protein, human; D009124:Muscle Proteins