Alternative titles; symbols
HGNC Approved Gene Symbol: KY
Cytogenetic location: 3q22.2 Genomic coordinates (GRCh38): 3:134,599,923-134,651,022 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q22.2 | Myopathy, myofibrillar, 7 | 617114 | Autosomal recessive | 3 |
Blanco et al. (2001) identified the mouse ky gene and the mutation underlying the kyphoscoliotic mouse. The ky transcript encodes a novel protein that is detected only in skeletal muscle and heart, and has a domain homologous to human transglutaminase (see 600238). The mutation is a dinucleotide deletion affecting codon 24, leading to a premature stop codon at position 105.
Straussberg et al. (2016) found expression of the KY gene at the sarcolemma in skeletal muscle.
Beatham et al. (2004) showed that KY interacted with several sarcomeric cytoskeletal proteins including filamin C (FLNC; 102565) and the slow isoform of the myosin-binding protein C (MYBPC1; 160794). A role for KY in regulating filamin C function in vivo was supported by expression analysis of filamin C in the KY-null mouse mutant, where distinct irregular subcellular localization of filamin C was found in subsets of muscle fibers, which appeared to be a specific outcome of KY deficiency. In vitro assays showed that KY has protease activity, and specific degradation of filamin C by KY was shown in transfected cells. Beatham et al. (2004) suggested that KY may be an intrinsic part of the protein networks underlying the molecular mechanism of several limb-girdle muscular dystrophies, particularly those where interactions between filamin C and disease-causing proteins have been shown.
By screening a radiation hybrid panel, Blanco et al. (2001) localized the human KY gene to chromosome 3q21.
Gross (2021) mapped the KY gene to chromosome 3q22.2 based on an alignment of the KY sequence (GenBank AK126993) with the genomic sequence (GRCh38).
Blanco et al. (1998) localized the ky locus to a small region of mouse chromosome 9.
In 2 brothers, born of consanguineous Arab Israeli parents, with myofibrillar myopathy-7 (MFM7; 617114), Straussberg et al. (2016) identified a homozygous truncating mutation in the KY gene (Y135X; 605739.0001). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Immunostaining showed absence of the KY protein in patient muscle, consistent with a loss of function. Electron microscopy of patient muscle showed unstructured core targetoid defects with streaming and thickening of the Z discs, as well as an enlarged endoplasmic reticulum, consistent with myofibrillar derangement.
In a 7.5-year-old girl, born of consanguineous Kurdish parents, with MFM7, Hedberg-Oldfors et al. (2016) identified a homozygous frameshift mutation in the KY gene (605739.0002). The mutation was found by whole-exome sequencing and segregated with the disorder in the family.
In a 29-year-old man with MFM7, who was born of consanguineous Iranian parents, Ebrahimzadeh-Vesal et al. (2018) identified a homozygous nonsense mutation in the KY gene (R139X; 605739.0003). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was also present in his affected sister. The parents and an unaffected sister were heterozygous for the mutation. Functional studies were not performed.
The kyphoscoliosis (ky) mouse mutant exhibits a primary degenerative myopathy preceding chronic thoracolumbar kyphoscoliosis. The histopathology of the ky mutant suggests that ky protein activity is crucial for normal muscle growth and function as well as the maturation and stabilization of the neuromuscular junction. Muscle hypertrophy in response to increasing demand is deficient in the ky mutant, whereas adaptive fiber type shifts take place (Blanco et al., 2001).
In 2 brothers, born of consanguineous Arab Israeli parents, with myofibrillar myopathy-7 (MFM7; 617114), Straussberg et al. (2016) identified a homozygous c.405C-A transversion (c.405C-A, NM_178554) in the KY gene, resulting in a tyr135-to-ter (Y135X) substitution. The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family and was not found in the ExAC or 1000 Genomes project database. Immunostaining showed absence of the KY protein in patient muscle, consistent with a loss of function.
In a 7.5-year-old girl, born of consanguineous Kurdish parents, with myofibrillar myopathy-7 (MFM7; 617114), Hedberg-Oldfors et al. (2016) identified a homozygous 1-bp deletion (c.1071delG, NM_178554.4) in the KY gene, resulting in a frameshift and premature termination (Thr358LeufsTer3). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. The mutant transcript was detected in patient skeletal muscle, indicating that it was not subject to nonsense-mediated mRNA decay, but the mutation was predicted to encode a truncated nonfunctional protein.
In a 29-year-old man with myofibrillar myopathy-7 (MFM7; 617114), who was born to consanguineous Iranian parents, Ebrahimzadeh-Vesal et al. (2018) identified a homozygous c.415C-T transition (c.415C-T, NM_178554) in exon 4 of the KY gene, resulting in an arg139-to-ter (R139X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated, nonfunctional protein. The variant had a frequency of 0.00008 in the NHLBI Exome Sequencing Project database and was absent in gnomAD.
Beatham, J., Romero, R., Townsend, S. K. M., Hacker, T., van der Ven, P. F. M., Blanco, G. Filamin C interacts with the muscular dystrophy KY protein and is abnormally distributed in mouse KY deficient muscle fibres. Hum. Molec. Genet. 13: 2863-2874, 2004. [PubMed: 15385448] [Full Text: https://doi.org/10.1093/hmg/ddh308]
Blanco, G., Coulton, G. R., Biggin, A., Grainge, C., Moss, J., Barrett, M., Berquin, A., Marechal, G., Skynner, M., van Mier, P., Nikitopoulou, A., Kraus, M., Ponting, C. P., Mason, R. M., Brown, S. D. M. The kyphoscoliosis (ky) mouse is deficient in hypertrophic responses and is caused by a mutation in a novel muscle-specific protein. Hum. Molec. Genet. 10: 9-16, 2001. [PubMed: 11136708] [Full Text: https://doi.org/10.1093/hmg/10.1.9]
Blanco, G., Nikitopoulou, A., Kraus, M., Mason, R. M., Coulton, G. R., Brown, S. D. A STS content physical and transcription map across the ky, kyphoscoliosis, nonrecombinant region. Genomics 54: 415-423, 1998. [PubMed: 9878244] [Full Text: https://doi.org/10.1006/geno.1998.5614]
Ebrahimzadeh-Vesal, R., Teymoori, A., Dourandish, A. M., Azimi-Nezhad, M. Identification of a novel nonsense mutation in kyphoscoliosis peptidase gene in an Iranian patient with myofibrillar myopathy. Genes Dis. 5: 331-334, 2018. [PubMed: 30591934] [Full Text: https://doi.org/10.1016/j.gendis.2018.09.004]
Gross, M. B. Personal Communication. Baltimore, Md. 3/1/2021.
Hedberg-Oldfors, C., Darin, N., Olsson Engman, M., Orfanos, Z., Thomsen, C., van der Ven, P. F. M., Oldfors, A. A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency. Europ. J. Hum. Genet. 24: 1771-1777, 2016. [PubMed: 27485408] [Full Text: https://doi.org/10.1038/ejhg.2016.98]
Straussberg, R., Schottmann, G., Sadeh, M., Gill, E., Seifert, F., Halevy, A., Qassem, K., Rendu, J., van der Ven, P. F. M., Stenzel, W., Schuelke, M. Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects. Acta Neuropath. 132: 475-478, 2016. [PubMed: 27484770] [Full Text: https://doi.org/10.1007/s00401-016-1602-9]