Alternative titles; symbols
HGNC Approved Gene Symbol: CHKB
SNOMEDCT: 1230273004;
Cytogenetic location: 22q13.33 Genomic coordinates (GRCh38) : 22:50,578,963-50,582,849 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.33 | Muscular dystrophy, congenital, megaconial type | 602541 | Autosomal recessive | 3 |
Choline kinases (EC 2.7.1.32), such as CHKB and CHKA (118491), catalyze phosphorylation of choline by ATP in the presence of Mg(2+), yielding phosphocholine and ADP. This step commits choline to the enzymatic pathway for biosynthesis of phosphatidylcholine (Ishidate, 1997; Aoyama et al., 2000).
By screening a placenta genomic DNA library with a partial CHKB genomic clone, followed by RT-PCR and 3-prime RACE of heart and skeletal muscle RNA, Yamazaki et al. (2000) cloned human CHKB, which they called CKEKB. The deduced 395-amino acid CHEKB protein has a calculated molecular mass of about 45 kD and is about 86% homologous to rat and mouse Ckekb. By RT-PCR of human heart and skeletal muscle mRNA, Yamazaki et al. (2000) also identified fusion transcripts in which 3-prime exons from the CKEKB gene were spliced to either exon 1A or exon 2 of the downstream MCPT1 gene (CPT1B; 601987).
Aoyama et al. (2000) cloned mouse Chekb and identified human CKEKB by database analysis. The deduced proteins contain several highly conserved domains, including a Brenner phosphotransferase consensus sequence involved in catalytic function.
Yamazaki et al. (2000) determined that the CHKB gene contains 11 exons.
By genomic sequence analysis, Yamazaki et al. (2000) mapped the CHKB gene to chromosome 22q13, less than 1 kb upstream of the CPT1B gene.
Based on the phenotype of the rostrocaudal muscular dystrophy (rmd) mouse due to a deletion in the Chkb gene (Sher et al., 2006), Mitsuhashi et al. (2011) screened the CHKB gene in 15 patients with megaconial-type congenital muscular dystrophy (MDCMC; 602541) and identified homozygous or compound heterozygous mutations in all patients (see, e.g., 612395.0001-612395.0005). Eleven mutations were identified, including 6 nonsense, 2 missense, a deletion, and 2 splice site mutations. Skeletal muscle biopsies had no detectable choline kinase (CHK) activity, consistent with a loss of function, and also showed decreased amounts of phosphatidylcholine, and CHKA was not detected in normal human muscle, suggesting that CHKB is the major isoform in skeletal muscle. The findings indicated that this muscle disease is caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the important role of phosphatidylcholine in muscle and brain.
Sher et al. (2006) reported a spontaneous autosomal recessive mouse model of rostrocaudal muscular dystrophy (rmd) characterized by early-onset of progressive muscle wasting and hindlimb weakness and an outward rotation of the forelimbs associated with defective bone morphology. Affected rmd/rmd mice developed severe hindlimb control by 2 to 3 months of age. Hindlimb muscles showed severe dystrophic features, with centralized nuclei, fatty infiltration, and loss of muscle fibers, with subtle disruption of the sarcolemmal membrane apparent on electron microscopy. However, affected muscles contained extremely large mitochondria without abnormal respiratory chain immunostaining in affected muscles. Positional cloning allowed identification of a 1.6-kb deletion in the Chkb gene as causative for the rmd phenotype. Western blot analysis confirmed complete loss of the Chkb protein, and there was decreased enzymatic activity of choline kinase and decreased levels of phosphatidylcholine.
In 2 unrelated Japanese patients with megaconial-type congenital muscular dystrophy (MDCMC; 602541) previously reported by Nishino et al. (1998), Mitsuhashi et al. (2011) identified a homozygous 810T-A transition in exon 7 of the CHKB gene, resulting in a tyr270-to-ter (Y270X) substitution. Skeletal muscle biopsy had no detectable choline kinase (CHK) activity, consistent with a loss of function.
In a Spanish boy with MDCMC and a combined defect of mitochondrial respiratory chain enzyme activity, Castro-Gago et al. (2014) identified a homozygous Y270X mutation (c.810T-A, NM_005198) in the CHKB gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Additional genetic causes for the respiratory chain deficiency were excluded, suggesting that a defect in phospholipid metabolism can result in mitochondrial dysfunction.
In 2 Japanese sibs with megaconial-type congenital muscular dystrophy (MDCMC; 602541) previously reported by Nishino et al. (1998), Mitsuhashi et al. (2011) identified compound heterozygosity for 2 mutations in the CHKB gene: a 116C-A transversion in exon 1, resulting in a ser39-to-ter (S39X) substitution, and 1-bp duplication (458dup; 612395.0003) in exon 3, resulting in a frameshift and premature termination after 57 amino acids. Skeletal muscle biopsy had no detectable CHK activity, consistent with a loss of function.
For discussion of the 1-bp duplication in the CHKB gene (458dup) that was found in compound heterozygous state in patients with megaconial-type congenital muscular dystrophy (MDCMC; 602541) by Mitsuhashi et al. (2011), see 612395.0002.
In a Turkish patient with megaconial-type congenital muscular dystrophy (MDCMC; 602541), Mitsuhashi et al. (2011) identified a homozygous 922C-T transition in exon 8 of the CHKB gene, resulting in a gln308-to-ter (Q308X) substitution.
In 3 unrelated Turkish patients with megaconial-type congenital muscular dystrophy (MDCMC; 602541), Mitsuhashi et al. (2011) identified a homozygous G-to-A transition (677+1G-A) in intron 5 of the CHKB gene, resulting in a splice site mutation.
Aoyama, C., Yamazaki, N., Terada, H., Ishidate, K. Structure and characterization of the genes for murine choline/ethanolamine kinase isozymes alpha and beta. J. Lipid Res. 41: 452-464, 2000. [PubMed: 10706593]
Castro-Gago, M., Dacruz-Alvarez, D., Pintos-Martinez, E., Beiras-Iglesias, A., Delmiro, A., Arenas, J., Martin, M. A., Martinez-Azorin, F. Exome sequencing identifies a CHKB mutation in Spanish patient with megaconial congenital muscular dystrophy and mtDNA depletion. Europ. J. Paediat. Neurol. 18: 796-800, 2014. [PubMed: 24997086] [Full Text: https://doi.org/10.1016/j.ejpn.2014.06.005]
Ishidate, K. Choline/ethanolamine kinase from mammalian tissues. Biochim. Biophys. Acta 1348: 70-78, 1997. [PubMed: 9370318] [Full Text: https://doi.org/10.1016/s0005-2760(97)00118-5]
Mitsuhashi, S., Ohkuma, A., Talim, B., Karahashi, M., Koumura, T., Aoyama, C., Kurihara, M., Quinlivan, R., Sewry, C., Mitsuhashi, H., Goto, K., Koksal, B., and 12 others. A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Am. J. Hum. Genet. 88: 845-851, 2011. [PubMed: 21665002] [Full Text: https://doi.org/10.1016/j.ajhg.2011.05.010]
Nishino, I., Kobayashi, O., Goto, Y.-I., Kurihara, M., Kumagai, K., Fujita, T., Hashimoto, K., Horai, S., Nonaka, I. A new congenital muscular dystrophy with mitochondrial structural abnormalities. Muscle Nerve 21: 40-47, 1998. [PubMed: 9427222] [Full Text: https://doi.org/10.1002/(sici)1097-4598(199801)21:1<40::aid-mus6>3.0.co;2-g]
Sher, R. B., Aoyama, C., Huebsch, K. A., Ji, S., Kerner, J., Yang, Y., Frankel, W. N., Hoppel, C. L., Wood, P. A., Vance, D. E., Cox, G. A. A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis. J. Biol. Chem. 281: 4938-4948, 2006. [PubMed: 16371353] [Full Text: https://doi.org/10.1074/jbc.M512578200]
Yamazaki, N., Shinohara, Y., Kajimoto, K., Shindo, M., Terada, H. Novel expression of equivocal messages containing both regions of choline/ethanolamine kinase and muscle type carnitine palmitoyltransferase I. J. Biol. Chem. 275: 31739-31746, 2000. [PubMed: 10918069] [Full Text: https://doi.org/10.1074/jbc.M006322200]