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MYO1A (myosin IA)

Written2013-12Diego Arango del Corro, Rocco Mazzolini
Group of Molecular Oncology, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital Research Institute, 08035 Barcelona, Spain

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMYHL
DFNA48
Other aliasBBMI
MIHC
HGNC (Hugo) MYO1A
LocusID (NCBI) 4640
Atlas_Id 47246
Location 12q13.3  [Link to chromosome band 12q13]
Location_base_pair Starts at 57028517 and ends at 57050765 bp from pter ( according to hg19-Feb_2009)  [Mapping MYO1A.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note Orientation: minus strand.

DNA/RNA

 
  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.

Protein

 
  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).
 
  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).
 
  Figure 4. Relative MYO1A mRNA levels in human tumors of different origin. Box-whisker plot of the gene's 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).
 
  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

 
  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

Note
  
Entity 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 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 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 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

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Epithelial polarity, villin expression, and enterocytic differentiation of cultured human colon carcinoma cells: a survey of twenty cell lines.
Chantret I, Barbat A, Dussaulx E, Brattain MG, Zweibaum A.
Cancer Res. 1988 Apr 1;48(7):1936-42.
PMID 3349466
 
The 110,000-dalton actin- and calmodulin-binding protein from intestinal brush border is a myosin-like ATPase.
Collins JH, Borysenko CW.
J Biol Chem. 1984 Nov 25;259(22):14128-35.
PMID 6094541
 
Mapping 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, Bretscher A.
Biochemistry. 1990 Dec 18;29(50):11089-94.
PMID 2271696
 
Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss.
Donaudy F, Ferrara A, Esposito L, Hertzano R, Ben-David O, Bell RE, Melchionda S, Zelante L, Avraham KB, Gasparini P.
Am J Hum Genet. 2003 Jun;72(6):1571-7. Epub 2003 May 6.
PMID 12736868
 
Myosin-I isozymes in neonatal rodent auditory and vestibular epithelia.
Dumont RA, Zhao YD, Holt JR, Bahler M, Gillespie PG.
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PMID 12486594
 
Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues.
Kilpinen S, Autio R, Ojala K, Iljin K, Bucher E, Sara H, Pisto T, Saarela M, Skotheim RI, Bjorkman M, Mpindi JP, Haapa-Paananen S, Vainio P, Edgren H, Wolf M, Astola J, Nees M, Hautaniemi S, Kallioniemi O.
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PMID 18803840
 
Myosins: tails (and heads) of functional diversity.
Krendel M, Mooseker MS.
Physiology (Bethesda). 2005 Aug;20:239-51. (REVIEW)
PMID 16024512
 
Identification and organization of the components in the isolated microvillus cytoskeleton.
Matsudaira PT, Burgess DR.
J Cell Biol. 1979 Dec;83(3):667-73.
PMID 574874
 
Brush border myosin Ia inactivation in gastric but not endometrial tumors.
Mazzolini R, Rodrigues P, Bazzocco S, Dopeso H, Ferreira AM, Mateo-Lozano S, Andretta E, Woerner SM, Alazzouzi H, Landolfi S, Hernandez-Losa J, Macaya I, Suzuki H, Ramon y Cajal S, Mooseker MS, Mariadason JM, Gebert J, Hofstra RM, Reventos J, Yamamoto H, Schwartz S Jr, Arango D.
Int J Cancer. 2013 Apr 15;132(8):1790-9. doi: 10.1002/ijc.27856. Epub 2012 Oct 20.
PMID 23002058
 
Leveraging the membrane - cytoskeleton interface with myosin-1.
McConnell RE, Tyska MJ.
Trends Cell Biol. 2010 Jul;20(7):418-26. doi: 10.1016/j.tcb.2010.04.004. Epub 2010 May 12. (REVIEW)
PMID 20471271
 
Myosin motor function: the ins and outs of actin-based membrane protrusions.
Nambiar R, McConnell RE, Tyska MJ.
Cell Mol Life Sci. 2010 Apr;67(8):1239-54. doi: 10.1007/s00018-009-0254-5. Epub 2010 Jan 27. (REVIEW)
PMID 20107861
 
Cloning and characterization of mouse brush border myosin-I in adult and embryonic intestine.
Skowron JF, Mooseker MS.
J Exp Zool. 1999 Feb 15;283(3):242-57.
PMID 9933937
 
Myosin-1a is critical for normal brush border structure and composition.
Tyska MJ, Mackey AT, Huang JD, Copeland NG, Jenkins NA, Mooseker MS.
Mol Biol Cell. 2005 May;16(5):2443-57. Epub 2005 Mar 9.
PMID 15758024
 
Localization of villin, a cytoskeletal protein specific to microvilli, in human ileum and colon and in colonic neoplasms.
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Gastroenterology. 1988 Feb;94(2):343-52.
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Citation

This paper should be referenced as such :
Arango, del Corro D ; Mazzolini, R
MYO1A (myosin IA)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(8):565-570.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/MYO1AID47246ch12q13.html


External links

Nomenclature
HGNC (Hugo)MYO1A   7595
Cards
AtlasMYO1AID47246ch12q13
Entrez_Gene (NCBI)MYO1A  4640  myosin IA
AliasesBBMI; DFNA48; MIHC; MYHL
GeneCards (Weizmann)MYO1A
Ensembl hg19 (Hinxton)ENSG00000166866 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000166866 [Gene_View]  chr12:57028517-57050765 [Contig_View]  MYO1A [Vega]
ICGC DataPortalENSG00000166866
TCGA cBioPortalMYO1A
AceView (NCBI)MYO1A
Genatlas (Paris)MYO1A
WikiGenes4640
SOURCE (Princeton)MYO1A
Genetics Home Reference (NIH)MYO1A
Genomic and cartography
GoldenPath hg38 (UCSC)MYO1A  -     chr12:57028517-57050765 -  12q13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MYO1A  -     12q13.3   [Description]    (hg19-Feb_2009)
EnsemblMYO1A - 12q13.3 [CytoView hg19]  MYO1A - 12q13.3 [CytoView hg38]
Mapping of homologs : NCBIMYO1A [Mapview hg19]  MYO1A [Mapview hg38]
OMIM601478   607841   
Gene and transcription
Genbank (Entrez)AF009961 AF105424 AF127026 AK300381 AK312431
RefSeq transcript (Entrez)NM_001256041 NM_005379
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)MYO1A
Cluster EST : UnigeneHs.5394 [ NCBI ]
CGAP (NCI)Hs.5394
Alternative Splicing GalleryENSG00000166866
Gene ExpressionMYO1A [ NCBI-GEO ]   MYO1A [ EBI - ARRAY_EXPRESS ]   MYO1A [ SEEK ]   MYO1A [ MEM ]
Gene Expression Viewer (FireBrowse)MYO1A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4640
GTEX Portal (Tissue expression)MYO1A
Human Protein AtlasENSG00000166866-MYO1A [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UBC5   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UBC5  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UBC5
Splice isoforms : SwissVarQ9UBC5
PhosPhoSitePlusQ9UBC5
Domaine pattern : Prosite (Expaxy)IQ (PS50096)    MYOSIN_MOTOR (PS51456)    TH1 (PS51757)   
Domains : Interpro (EBI)IQ_motif_EF-hand-BS    Myosin_head_motor_dom    Myosin_TH1    P-loop_NTPase   
Domain families : Pfam (Sanger)IQ (PF00612)    Myosin_head (PF00063)    Myosin_TH1 (PF06017)   
Domain families : Pfam (NCBI)pfam00612    pfam00063    pfam06017   
Domain families : Smart (EMBL)IQ (SM00015)  MYSc (SM00242)  
Conserved Domain (NCBI)MYO1A
DMDM Disease mutations4640
Blocks (Seattle)MYO1A
SuperfamilyQ9UBC5
Human Protein Atlas [tissue]ENSG00000166866-MYO1A [tissue]
Peptide AtlasQ9UBC5
HPRD08371
IPIIPI00294386   IPI01011230   IPI01024989   IPI01025342   IPI00853575   
Protein Interaction databases
DIP (DOE-UCLA)Q9UBC5
IntAct (EBI)Q9UBC5
FunCoupENSG00000166866
BioGRIDMYO1A
STRING (EMBL)MYO1A
ZODIACMYO1A
Ontologies - Pathways
QuickGOQ9UBC5
Ontology : AmiGOmotor activity  calmodulin binding  ATP binding  cytoplasm  microvillus  brush border  sensory perception of sound  basal plasma membrane  basolateral plasma membrane  apical plasma membrane  lateral plasma membrane  myosin complex  microvillus assembly  cortical actin cytoskeleton  filamentous actin  plasma membrane raft  actin filament binding  vesicle localization  
Ontology : EGO-EBImotor activity  calmodulin binding  ATP binding  cytoplasm  microvillus  brush border  sensory perception of sound  basal plasma membrane  basolateral plasma membrane  apical plasma membrane  lateral plasma membrane  myosin complex  microvillus assembly  cortical actin cytoskeleton  filamentous actin  plasma membrane raft  actin filament binding  vesicle localization  
NDEx NetworkMYO1A
Atlas of Cancer Signalling NetworkMYO1A
Wikipedia pathwaysMYO1A
Orthology - Evolution
OrthoDB4640
GeneTree (enSembl)ENSG00000166866
Phylogenetic Trees/Animal Genes : TreeFamMYO1A
HOVERGENQ9UBC5
HOGENOMQ9UBC5
Homologs : HomoloGeneMYO1A
Homology/Alignments : Family Browser (UCSC)MYO1A
Gene fusions - Rearrangements
Tumor Fusion PortalMYO1A
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerMYO1A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)MYO1A
dbVarMYO1A
ClinVarMYO1A
1000_GenomesMYO1A 
Exome Variant ServerMYO1A
ExAC (Exome Aggregation Consortium)ENSG00000166866
GNOMAD BrowserENSG00000166866
Genetic variants : HAPMAP4640
Genomic Variants (DGV)MYO1A [DGVbeta]
DECIPHERMYO1A [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisMYO1A 
Mutations
ICGC Data PortalMYO1A 
TCGA Data PortalMYO1A 
Broad Tumor PortalMYO1A
OASIS PortalMYO1A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICMYO1A  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDMYO1A
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
BioMutasearch MYO1A
DgiDB (Drug Gene Interaction Database)MYO1A
DoCM (Curated mutations)MYO1A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)MYO1A (select a term)
intoGenMYO1A
NCG5 (London)MYO1A
Cancer3DMYO1A(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601478    607841   
Orphanet12046   
DisGeNETMYO1A
MedgenMYO1A
Genetic Testing Registry MYO1A
NextProtQ9UBC5 [Medical]
TSGene4640
GENETestsMYO1A
Target ValidationMYO1A
Huge Navigator MYO1A [HugePedia]
snp3D : Map Gene to Disease4640
BioCentury BCIQMYO1A
ClinGenMYO1A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4640
Chemical/Pharm GKB GenePA31397
Clinical trialMYO1A
Miscellaneous
canSAR (ICR)MYO1A (select the gene name)
Probes
Litterature
PubMed31 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineMYO1A
EVEXMYO1A
GoPubMedMYO1A
iHOPMYO1A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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