HGNC Approved Gene Symbol: KBTBD13
Cytogenetic location: 15q22.31 Genomic coordinates (GRCh38) : 15:65,076,746-65,079,948 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q22.31 | Nemaline myopathy 6, autosomal dominant | 609273 | Autosomal dominant | 3 |
KBTBD13 is an actin-binding protein that modulates muscle kinetics (de Winter et al., 2020).
By searching a region of chromosome 15 linked to nemaline myopathy (NEM6; 609273), followed by RT-PCR of skeletal muscle RNA, Sambuughin et al. (2010) cloned KBTBD13. The deduced 458-amino acid protein has a calculated molecular mass of 49 kD. KBTBD13 has an N-terminal BTB/POZ domain, followed by a central alpha-helical linker region and a C-terminal Kelch repeat domain that contains 5 repeats and is predicted to form a beta-propeller structure. Northern blot analysis detected a 3.5-kb KBTBD13 transcript in skeletal muscle. RT-PCR of mouse tissues detected Kbtbd13 in skeletal muscle, heart, and lung, with very low expression in other tissues examined. Epitope-tagged KBTBD13 localized in a punctate cytoplasmic distribution in transfected C2C12 mouse myotubes and embryonic mouse cardiomyocytes.
Sambuughin et al. (2010) determined that the KBTBD13 gene contains a single exon.
By genomic sequence analysis, Sambuughin et al. (2010) mapped the KBTBD13 gene to chromosome 15q22.31.
In affected members of 4 unrelated families with nemaline myopathy-6 (NEM6; 609273), Sambuughin et al. (2010) identified heterozygous mutations in the KBTBD13 gene (613727.0001 and 613727.0002). Another patient with sporadic disease carried a third heterozygous mutation (613727.0003).
De Winter et al. (2020) found that mice with a homozygous Kbtbd13 arg408-to-cys (R408C; 613727.0002) knockin mutation were born at significantly higher than mendelian ratio, with higher body weight than wildtype and pathology consistent with human NEM6. Muscles of knockin mice displayed slower relaxation kinetics and stiffer thin filaments compared with wildtype. In contrast, Kbtbd13 -/- mice were born at close to mendelian ratio and had lower body weight and normal relaxation kinetics compared with wildtype. Homology modeling, pull-down assays, and localization studies revealed that wildtype Kbtbd13 interacted and colocalized with action in thin filaments of muscle. However, the Kbtbd13 R408C mutant directly increased stiffness of actin filaments, and the increased stiffness of thin filaments slowed down relaxation of mouse and human muscle fibers.
In affected members of a Spanish family with autosomal dominant nemaline myopathy-6 (NEM6; 609273), previously reported by Olive et al. (2010), Sambuughin et al. (2010) identified a heterozygous c.1170G-C transversion in the KBTBD13 gene, resulting in a lys390-to-asn (K390N) substitution at a highly conserved residue in the fifth kelch repeat, predicted to damage the strands of the beta-propeller blades. The mutation was not found in 80 Spanish, 52 Dutch, or 84 European Americans.
In affected members of 3 unrelated families with autosomal dominant nemaline myopathy-6 (NEM6; 609273), previously reported by Gommans et al. (2003), Sambuughin et al. (2010) identified a heterozygous c.1222C-T transition in the KBTBD13 gene, resulting in an arg408-to-cys (R408C) substitution at a highly conserved residue in the fifth kelch repeat, predicted to damage the strands of the beta-propeller blades. The families were of Dutch, Australian Dutch, and Australian Belgian origin, and haplotype analysis indicated a founder effect among the 3 families. The mutation was not found in 80 Spanish, 52 Dutch, or 84 European Americans.
In an Australian patient with nemaline myopathy-6 (NEM6; 609273), Sambuughin et al. (2010) identified a heterozygous c.742C-A transversion in the KBTBD13 gene, resulting in an arg248-to-ser (R248S) substitution at a highly conserved residue in the second kelch repeat, predicted to damage the strands of the beta-propeller blades. The mutation was not found in 148 Australian or 52 Dutch controls.
de Winter, J. M., Molenaar, J. P., Yuen, M., van der Pijl, R., Shen, S., Conijn, S., van de Locht, M., Willigenburg, M., Bogaards, S. J. P., van Kleef, E. S. B., Lassche, S., Persson, M., and 29 others. KBTBD13 is an actin-binding protein that modulates muscle kinetics. J. Clin. Invest. 130: 754-767, 2020. Note: Erratum: J. Clin. Invest. 134: e179111, 2024. [PubMed: 31671076] [Full Text: https://doi.org/10.1172/JCI124000]
Gommans, I. M. P., Davis, M., Saar, K., Lammens, M., Mastaglia, F., Lamont, P., van Duijnhoven, G., ter Laak, H. J., Reis, A., Vogels, O. J. M., Laing, N., van Engelen, B. G. M., Kremer, H. A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions. Brain 126: 1545-1551, 2003. Note: Erratum: Brain 126: 2115 only, 2003. [PubMed: 12805120] [Full Text: https://doi.org/10.1093/brain/awg162]
Olive, M., Goldfarb, L. G., Lee, H. S., Odgerel, Z., Blokhin, A., Gonzalez-Mera, L., Moreno, D., Laing, N. G., Sambuughin, N. Nemaline myopathy type 6: clinical and myopathological features. Muscle Nerve 42: 901-907, 2010. [PubMed: 21104864] [Full Text: https://doi.org/10.1002/mus.21788]
Sambuughin, N., Yau, K. S., Olive, M., Duff, R. M., Bayarsaikhan, M., Lu, S., Gonzalez-Mera, L., Sivadorai, P., Nowak, K. J., Ravenscroft, G., Mastaglia, F. L., North, K. N., and 9 others. Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. Am. J. Hum. Genet. 87: 842-847, 2010. Note: Erratum: Am. J. Hum. Genet. 88: 122 only, 2011. [PubMed: 21109227] [Full Text: https://doi.org/10.1016/j.ajhg.2010.10.020]