Alternative titles; symbolsMYOSIN IC, FORMERLY; MYO1C, FORMERLYHGNC Approved Gene Symbol: MYO1ECytogenetic location: 15q22.2 Genomic coordinates (GRCh38): 15...
Alternative titles; symbols
HGNC Approved Gene Symbol: MYO1E
Cytogenetic location: 15q22.2 Genomic coordinates (GRCh38): 15:59,132,433-59,372,870 (from NCBI)
The MYO1E gene encodes a nonmuscle membrane-associated class I myosin with a motor-head domain that binds ATP and F-actin, a calmodulin-binding neck domain, and a tail domain. MYO1E is expressed in the podocyte membrane in the renal glomerulus (summary by Mele et al., 2011).
▼ Cloning and Expression
Bement et al. (1994) cloned a human unconventional myosin gene, MYO1E, encoding a predicted 127-kD polypeptide of 1,109 amino acids. The gene, which they designated myosin IC, contains a characteristic N-terminal myosin head, a single 'IQ motif' predicted to bind a single myosin light chain, and a C-terminal tail with a putative membrane-binding site. They also noted the presence of a C-terminal src-homology domain, reminiscent of 'long-tailed' myosins I from amoeboid organisms. By Northern analysis, Bement et al. (1994) detected ubiquitous expression of MYO1E.
Hasson et al. (1996) used fluorescence in situ hybridization to map 4 unconventional myosin loci in humans: MYO1E (formerly MYO1C), MYO1A (601478), MYO1F (601480), and MYO10 (601481). The MYO1E gene was found to be located on chromosome 15q21-q22 in the precise location predicted from its location on chromosome 9 of the mouse.
▼ Gene Function
Mele et al. (2011) showed that MYO1E localizes to the cytoplasmic side of the podocyte membrane in glomeruli of human kidney biopsy specimens, with enrichment at the lamellipodia tips. MYO1E localized at the tips of F-actin bundles. The findings implicated MYO1E as a key component of the foot-process cytoskeleton, important for podocyte structure in the glomerulus. Nonmuscle myosins, such as MYO1E, generate tension that helps glomerular capillaries resist hydrostatic pressure at the glomerular filtration barrier.
▼ Molecular Genetics
By genomewide linkage analysis followed by high-throughput sequencing of a consanguineous Italian family with focal segmental glomerulosclerosis-6 (FSGS6; 614131), Mele et al. (2011) identified a homozygous mutation in the MYO1E gene (A159P; 601479.0001). Sequencing of the MYO1E gene in 52 additional patients with FSGS or mesangial sclerosis identified a homozygous truncating mutation (Y695X; 601479.0002) in a Turkish girl with FSGS. Cellular studies showed that the A159P-mutant protein mislocalized to the cytoplasm, did not colocalize with F-action, and was unable to promote podocyte migration.
▼ Animal Model
In mice, Krendel et al. (2009) showed that Myo1e localizes to kidney podocytes. Myo1e-knockout mice developed proteinuria and hematuria associated with chronic renal failure, indicating a defect in the glomerular filtration barrier. Renal biopsies showed focal segmental glomerulosclerosis and interstitial fibrosis. Ultrastructural studies showed changes characteristic of glomerular disease, including a thickened and disorganized glomerular basement membrane, flattened, effaced podocyte foot processes, and signs of tubular injury. These defects were not present at birth but developed in the first weeks of life. The findings indicated that Myo1e plays an important role in podocyte function and normal glomerular filtration, and underscored the importance of the actin cytoskeleton in podocyte biology.
▼ ALLELIC VARIANTS ( 2 Selected Examples):
.0001 FOCAL SEGMENTAL GLOMERULOSCLEROSIS 6
In 3 sibs, born of consanguineous Italian parents, with focal segmental glomerulosclerosis-6 (FSGS6; 614131) causing nephrotic syndrome and various degrees of renal failure, Mele et al. (2011) identified a homozygous 475G-C transversion in exon 6 of the MYO1E gene, resulting in an ala159-to-pro (A159P) substitution in a highly conserved residue within the switch-1 loop of the motor-head domain. This region is in the ATP-binding pocket close to the actin-binding domain. Each unaffected parent was heterozygous for the mutation, which was not found in 764 control chromosomes. Human podocytes transfected with the A159P-mutant protein showed diffuse cytoplasmic localization with a punctate pattern, whereas wildtype MYO1E localized to the plasma membrane. The mutant protein did not stain with an anti-MYO1E antibody, suggesting conformational changes of the mutant protein, did not colocalize with F-action, and was unable to promote podocyte migration.
.0002 FOCAL SEGMENTAL GLOMERULOSCLEROSIS 6
In a Turkish girl with focal segmental glomerulosclerosis-6 (614131) causing nephrotic syndrome, Mele et al. (2011) identified a homozygous 2085T-G transversion in the MYO1E gene, resulting in a tyr695-to-ter (Y695X) substitution at the start of the calmodulin-binding neck domain. Each unaffected parent was heterozygous for the mutation, which was not found in 968 control chromosomes. The mutation was predicted to result in a nonfunctional protein.