Alternative titles; symbols
HGNC Approved Gene Symbol: MYO9B
Cytogenetic location: 19p13.11 Genomic coordinates (GRCh38): 19:17,075,777-17,213,286 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
19p13.11 | {Celiac disease, susceptibility to, 4} | 609753 | 3 |
For background information on myosins, see MYO1A (601478).
Wirth et al. (1996) isolated cDNAs encoding human myosin IXB (MYO9B) from liver and small intestine libraries. The cDNAs encode a 2,022-amino acid protein with a predicted mass of 229 kD. Like other myosins, MYO9B contains an N-terminal head or motor domain, a neck domain containing 4 tandemly repeated IQ motifs, and a large C-terminal tail. Compared to conventional myosins, the MYO9B head region contains several unusual insertions and the tail region contains a putative GTPase-activating protein domain and putative binding domains for zinc and diacylglycerol. MYO9B and its rat homolog, myr5, have regions of significant sequence divergence at their N and C termini. Wirth et al. (1996) suggested that the rat and human cDNAs may represent alternate splice variants. Northern blot analysis revealed that the gene is expressed as an 8-kb transcript with highest levels of expression observed in peripheral blood leukocytes and moderate expression in thymus and spleen. Wirth et al. (1996) found that expression of the MYO9B protein increased 4.7-fold following TPA-induced differentiation of HL-60 myelocytes into macrophage-like cells. Wirth et al. (1996) suggested that MYO9B may have a role in actin-based processes in myeloid cells.
Post et al. (1998) identified a long variant of MYO9B that replaces the last 99 amino acids of the sequence reported by Wirth et al. (1996) with a different 228-amino acid C-terminal domain. Immunoblot analysis showed expression of 240- and 228-kD proteins.
Bahler et al. (1997) used fluorescence in situ hybridization to map the MYO9B gene to chromosome 19p13.2-p13.1. Cosmid mapping further refined this localization to 19p13.1, approximately 800 kb proximal to the MEL gene (165040) and approximately 100 kb distal to the ERBAL2 (132880) gene.
Immunoblot analysis by Post et al. (1998) showed that MYO9B binds calmodulin (CALM1; 114180) through IQ motifs located in its neck domain. Functional analysis indicated that MYO9B is an active motor that, like other CALM1-containing myosins, exhibits maximal velocity of actin filaments in the absence of calcium. Post et al. (1998) concluded that MYO9B contains calmodulin light chains and is a calcium-regulated, mechanochemically active motor that exhibits RHOGAP (see 602732) activity.
Inoue et al. (2002) determined that MYO9B, a single-headed myosin, moves processively on actin filaments as a minus-end-directed motor. Thus, like MYO6 (600970), MYO9B moves in the reverse direction. Post et al. (2002) also performed functional analyses and concluded that MYO9B is single-headed and, like MYO5A (160777), is a processive actin-based motor.
Using yeast 2-hybrid analysis, coimmunoprecipitation analysis, and in vitro pull-down assays, Saeki et al. (2005) found that rat and human BIG1 (ARFGEF1; 604141) bound the tail domain of MYO9B. BIG1 and MYO9B bound with a 1-to-1 stoichiometry, and mutation analysis showed that BIG1 bound specifically to the zinc finger/GAP domain of MYO9B. Binding of BIG1 to MYO9B interfered with binding of RhoA (165390) to MYO9B and inhibited the Rho-GAP activity of MYO9B in a dose-dependent manner. Likewise, RhoA inhibited binding of BIG1 to MYO9B.
Celiac disease (212750), one of the best understood immune-related disorders, presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Monsuur et al. (2005) reported significant and replicable association of celiac disease with a common variant located in intron 28 of the MYO9B gene (602129.0001). The unconventional myosin molecule encoded by MYO9B has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele had a 2.3-times higher risk of celiac disease. The result was suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier.
Monsuur et al. (2005) found that the presence of the A allele of rs2305764 disposes to a higher risk of celiac disease (CELIAC4; 609753), independent of variation in 5 other SNPs located in a 19-kb region. This SNP is located in the 3-part of the MYO9B gene. Class IX myosin molecules are unique in comparison with other myosin classes because they contain a Rho-GTPase-activating domain within their tails. This GTPase activity converts active Rho-GTP into inactive Rho-GDP, thereby downregulating Rho-dependent signaling pathways. Rho-family GTPases are involved in remodeling of the cytoskeleton and tight junction assembly, both of which result in enhanced epithelial paracellular permeability. Monsuur et al. (2005) speculated that a genetic variant in the 3-prime part of MYO9B leads to an impaired interaction with RhoA (165390), thereby perturbing tight junction gait and fence function. Hence, a subtle, underlying intestinal barrier abnormality may be involved in the etiology of celiac disease, which is in line with the observation of intestinal permeability in individuals with celiac disease with normal histology (e.g., Smecuol et al., 2005).
Bahler, M., Kehrer, I., Gordon, L., Stoffler, H.-E., Olsen, A. S. Physical mapping of human myosin-IXB (MYO9B), the human orthologue of the rat myosin myr 5, to chromosome 19p13.1. Genomics 43: 107-109, 1997. [PubMed: 9226381] [Full Text: https://doi.org/10.1006/geno.1997.4776]
Inoue, A., Saito, J., Ikebe, R., Ikebe, M. Myosin IXb is a single-headed minus-end-directed processive motor. Nature Cell Biol. 4: 302-306, 2002. [PubMed: 11901422] [Full Text: https://doi.org/10.1038/ncb774]
Monsuur, A. J., de Bakker, P. I. W., Alizadeh, B. Z., Zhernakova, A., Bevova, M. R., Strengman, E., Franke, L., van't Slot, R., van Belzen, M. J., Lavrijsen, I. C. M., Diosdado, B., Daly, M. J., Mulder, C. J. J., Mearin, M. L., Meijer, J. W. R., Meijer, G. A., van Oort, E., Wapenaar, M. C., Koeleman, B. P. C., Wijmenga, C. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect. Nature Genet. 37: 1341-1344, 2005. [PubMed: 16282976] [Full Text: https://doi.org/10.1038/ng1680]
Post, P. L., Bokoch, G. M., Mooseker, M. S. Human myosin-IXb is a mechanochemically active motor and a GAP for rho. J. Cell Sci. 111: 941-950, 1998. [PubMed: 9490638] [Full Text: https://doi.org/10.1242/jcs.111.7.941]
Post, P. L., Tyska, M. J., O'Connell, C. B., Johung, K., Hayward, A., Mooseker, M. S. Myosin-IXb is a single-headed and processive motor. J. Biol. Chem. 277: 11679-11683, 2002. [PubMed: 11801597] [Full Text: https://doi.org/10.1074/jbc.M111173200]
Saeki, N., Tokuo, H., Ikebe, M. BIG1 is a binding partner of myosin IXb and regulates its Rho-GTPase activating protein activity. J. Biol. Chem. 280: 10128-10134, 2005. [PubMed: 15644318] [Full Text: https://doi.org/10.1074/jbc.M413415200]
Smecuol, E., Sugai, E., Niveloni, S., Vazquez, H., Pedreira, S., Mazure, R., Moreno, M. L., Label, M., Maurino, E., Fasano, A., Meddings, J., Bai, J. C. Permeability, zonulin production, and enteropathy in dermatitis herpetiformis. Clin. Gastroent. Hepatol. 3: 335-341, 2005.
Wirth, J. A., Jensen, K. A., Post, P. L., Bement, W. M., Mooseker, M. S. Human myosin-IXb, an unconventional myosin with a chimerin-like rho/rac GTPase-activating protein domain in its tail. J. Cell Sci. 109: 653-661, 1996. [PubMed: 8907710] [Full Text: https://doi.org/10.1242/jcs.109.3.653]