MYO1A (myosin IA)

2013-12-01   Diego Arango del Corro , Rocco Mazzolini 

Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall dHebron University Hospital Research Institute, 08035 Barcelona, Spain

Identity

HGNC
LOCATION
12q13.3
LOCUSID
ALIAS
BBMI,DFNA48,MIHC,MYHL

DNA/RNA

Atlas Image
Figure 1. Diagram of DNA/RNA.

Description

There are several transcripts described for MYO1A. The two transcripts better characterized contain 28 and 29 exons spanning over 21 kb and both code for an identical protein of 1043 amino acids.

Proteins

Atlas Image
Figure 2. Protein structure of MYO1A.

Description

The protein encoded by the MYOSIN-IA gene belongs to the myosin superfamily. Like all myosin-1 isoforms, MYO1A contain these three core domains (figure 2): an N-terminal motor domain that coordinates ATP hydrolysis with actin binding and force generation; a central neck region made up of varying numbers of IQ motifs, which bind calmodulin or calmodulin-like proteins; and a tail region, which includes a highly basic C-terminal tail homology 1 (TH1) domain that is responsible for membrane binding (Coluccio and Bretscher, 1990; Krendel and Mooseker, 2005; McConnell and Tyska, 2010; Nambiar et al., 2010).
Atlas Image
Figure 3. Relative MYO1A mRNA levels in human normal tissues. MYO1A mRNA levels in human normal and tumor samples were obtained from a collection of 667 normal human samples from different tissues (Gene Expression Omnibus: GSE7307) and 10000 normal and tumor samples from GeneSapiens.org (Kilpinen et al., 2008).

Expression

Myo1a is highly expressed in the enterocytes that line the mucosa of the small intestine (Matsudaira and Burgess, 1979; Skowron and Mooseker, 1999). Expression of MYO1A has also been observed at relatively high levels in gastric epithelium when compared to other organs such as endometrium, myometrium, ovary and prostate (figure 3). In tumor samples, MYO1A mRNA expression in human gastric adenocarcinomas is comparable to intestinal adenocarcinomas, and significantly higher than in other tumor types (Mazzolini et al., 2013) (figure 4). Myo1a transcripts are also present in rodent inner ear at low level (Dumont et al., 2002).
Atlas Image
Figure 4. Relative MYO1A mRNA levels in human tumors of different origin. Box-whisker plot of the genes expression in cancer tissues. The bottom of the box is the 25th percentile of the data, the top of the box is the 75th percentile, and the vertical red line is the median. The whiskers extend to 1.5 times the interquartile range from the edges of the box, and any data points beyond this are considered outliers, marked by hollow circles. Filled grey bars are gastrointestinal carcinomas.

Localisation

Myo1a localizes to the cellular membrane through to the C-terminal tail domain. In the enterocytes that line the mucosa of the small intestine, MYO1A localizes to the apical brush border membrane (Matsudaira and Burgess, 1979; Collins and Borysenko, 1984; Skowron and Mooseker, 1999) (figure 5).
Atlas Image
Figure 5. MYO1A localizes to the apical membrane of intestinal epithelial cells. MYO1A-GFP was transfected into the colon cancer cell line Caco-2. The image was taken by confocal microscopy and represents an orthogonal stuck of a monolayer of cells. (A) Actin staining with rhodamine-phalloidin shows the apical and baso-lateral membtanes of the cells. (B) EGFP-MYO1A localizing in the apical membrane. (C) Overlay (modified from Mazzolini et al., 2012).

Function

Myosin Ia (MYO1A) is a major component of the cytoskeleton that underlies and supports the apical brush border of the enterocytes. MYO1A forms a spiral array of bridges that links the microvillar actin core to the membrane (Chantret et al., 1988; West et al., 1988; Beaulieu et al., 1990). Here, Myosin-1a plays a critical role in maintaining the brush border composition, structure, and regulating the microvillar membrane tension (Tyska et al., 2005; Nambiar et al., 2009), Myo1a also plays a role in powering the release of vesicles from the tips of the microvilli (McConnell et al., 2009).

Mutations

Atlas Image
Table 1. MYO1A mutations related to sensorineural bilateral hearing loss (Donaudy et al., 2003).
Figure 6. Somatic mutations of MYO1AA7MUT. (A) Frameshift mutations in the A8 track in Exon 28 of MYO1A. (B) Co-transfection of wild type EGFP-MYO1Awt and mutant ERFP-MYO1AA7MUT demonstrated that the mutant protein mislocalized to the cytoplasm of undifferentiated Caco2 cells (modified from Mazzolini et al., 2012). (C) Localization of additional mutations found in colorectal tumors without microsatellite instability.

Germinal

The following germinal mutations have been reported in eight unrelated patients coming from central and southern Italy and affected by sensorineural bilateral hearing loss of variable degree: one nonsense mutation, one trinucleotide insertion leading to an additional amino acid, and six missense mutations (Donaudy et al., 2003) (table 1).

Somatic

Mazzolini et al. reported frequent frame-shift somatic mutations in colorectal and gastric cancer. These mutations were found with the following frequencies: 44,4% (16 of 36) in microsatellite-instable colorectal cancer cell lines; 31,3% (42 of 134) in primary colon tumors; 46,8% (22/47) in gastric microsatellite-instable primary tumors. No mutations were observed in the matching healthy intestinal mucosa.
All the mutations observed were insertions or deletions in an A8 microsatellite tract located in exon 28. The most frequent mutation is the deletion of one A (MYO1AA7MUT). All the mutations found appeared to be heterozygous as the wild type allele was also visible in all cases (figure 6, panel A). The MYO1AA7MUT mutation causes sub-cellular mislocalization (figure 6, panel B) and decreased stability of Myosin-1a (Mazzolini et al., 2012; Mazzolini et al., 2013). Additional mutations have been found in colorectal tumors without microsatellite instability (TCGA; figure 6, panel C).

Implicated in

Entity name
Colorectal cancer
Note
The brush border protein Myosin Ia (MYO1A) has been demonstrated to be important for polarization and differentiation of colon cancer cells and is frequently inactivated in colorectal tumors by genetic and epigenetic mechanisms. Mazzolini et al. reported MYO1A frame-shift mutations in 32% (37 of 116) of the colorectal tumors with microsatellite instability. Evidence of promoter methylation was observed in a significant proportion of colon cancer cell lines and primary colorectal tumors.
The loss of polarization/differentiation resulting from MYO1A inactivation is associated with higher tumor growth in soft agar and in a xenograft model. In addition, the progression of genetically and carcinogen initiated intestinal tumors was significantly accelerated in Myo1a knockout mice compared with Myo1a wild-type animals. Moreover, MYO1A tumor expression was found to be an independent prognostic factor for colorectal cancer patients. Patients with low MYO1A tumor protein levels had significantly shorter disease-free and overall survival compared with patients with high MYO1A (logrank test P = 0.004 and P = 0.009, respectively). The median time-to-disease recurrence in patients with low MYO1A was 1 y, compared with >9 y in the group of patients with high MYO1A. These results identified MYO1A as a tumor-suppressor gene in colorectal cancer and demonstrate that the loss of structural brush border proteins involved in cell polarity are important for tumor development (Mazzolini et al., 2012).
Entity name
Gastric cancer
Note
Frame-shift somatic mutations have been reported in 46,8% (22/47) of gastric microsatellite-instable primary tumors. Frequent MYO1A promoter hypermethylation was also found in gastric tumors (Mazzolini et al., 2013).
Entity name
Endometrial cancer
Note
Rare mutations have been reported in 6,2% (3/48) of endometrial microsatellite-instable primary tumors (Mazzolini et al., 2013). The low frequency of this mutation in endometrial tumor is likely to reflect the background mutation rate occurring in endometrial MSI tumors.
Entity name
Nonsyndromic hearing loss
Note
MYO1A, which is located within the DFNA48 locus, was the first myosin I family member found to be involved in causing deafness and may be a major contributor to autosomal dominant-hearing loss. Several mutations in the MYO1A gene were found to be associated with hearing loss (table 1) (Donaudy et al., 2003). In particular, the substitution E385D has been characterized to disrupt the mechanochemical coupling and subcellular targeting of Myosin-1a (Yengo et al., 2008).

Bibliography

Pubmed IDLast YearTitleAuthors
16925461990Detection and characterization of sucrase-isomaltase in adult human colon and in colonic polyps.Beaulieu JF et al
33494661988Epithelial polarity, villin expression, and enterocytic differentiation of cultured human colon carcinoma cells: a survey of twenty cell lines.Chantret I et al
60945411984The 110,000-dalton actin- and calmodulin-binding protein from intestinal brush border is a myosin-like ATPase.Collins JH et al
22716961990Mapping of the microvillar 110K-calmodulin complex (brush border myosin I). Identification of fragments containing the catalytic and F-actin-binding sites and demonstration of a calcium ion dependent conformational change.Coluccio LM et al
127368682003Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss.Donaudy F et al
124865942002Myosin-I isozymes in neonatal rodent auditory and vestibular epithelia.Dumont RA et al
188038402008Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues.Kilpinen S et al
160245122005Myosins: tails (and heads) of functional diversity.Krendel M et al
5748741979Identification and organization of the components in the isolated microvillus cytoskeleton.Matsudaira PT et al
230020582013Brush border myosin Ia inactivation in gastric but not endometrial tumors.Mazzolini R et al
204712712010Leveraging the membrane - cytoskeleton interface with myosin-1.McConnell RE et al
201078612010Myosin motor function: the ins and outs of actin-based membrane protrusions.Nambiar R et al
99339371999Cloning and characterization of mouse brush border myosin-I in adult and embryonic intestine.Skowron JF et al
157580242005Myosin-1a is critical for normal brush border structure and composition.Tyska MJ et al
33353111988Localization of villin, a cytoskeletal protein specific to microvilli, in human ileum and colon and in colonic neoplasms.West AB et al
179819002008Human deafness mutation E385D disrupts the mechanochemical coupling and subcellular targeting of myosin-1a.Yengo CM et al

Other Information

Locus ID:

NCBI: 4640
MIM: 601478
HGNC: 7595
Ensembl: ENSG00000166866

Variants:

dbSNP: 4640
ClinVar: 4640
TCGA: ENSG00000166866
COSMIC: MYO1A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000166866ENST00000300119Q9UBC5
ENSG00000166866ENST00000433964C9JU63
ENSG00000166866ENST00000442789Q9UBC5
ENSG00000166866ENST00000492945G3V587
ENSG00000166866ENST00000554234G3V342

Expression (GTEx)

0
50
100
150

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
185997912008Myosin I can act as a molecular force sensor.99
119168462002MYO1A (brush border myosin I) dynamics in the brush border of LLC-PK1-CL4 cells.63
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
127368682003Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss.37
169368152006From transcription to transport: emerging roles for nuclear myosin I.23
223672062012Myosin-1A targets to microvilli using multiple membrane binding motifs in the tail homology 1 (TH1) domain.22
223076082012Brush border myosin Ia has tumor suppressor activity in the intestine.19
246161532014Targeted and genomewide NGS data disqualify mutations in MYO1A, the "DFNA48 gene", as a cause of deafness.15
179819002008Human deafness mutation E385D disrupts the mechanochemical coupling and subcellular targeting of myosin-1a.8
230020582013Brush border myosin Ia inactivation in gastric but not endometrial tumors.6

Citation

Diego Arango del Corro ; Rocco Mazzolini

MYO1A (myosin IA)

Atlas Genet Cytogenet Oncol Haematol. 2013-12-01

Online version: http://atlasgeneticsoncology.org/gene/47246/myo1a