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|Coordinate||98,085,466 bp (GRCm38)|
|Base Change||A ⇒ C (forward strand)|
|Gene Name||myosin VIIA|
|Synonym(s)||Myo7, nmf371, polka, Hdb, USH1B|
|Chromosomal Location||98,051,060-98,119,524 bp (-)|
|MGI Phenotype||Homozygotes for spontaneous and chemically induced mutations exhibit deafness, hyperactivity, head-shaking, and circling, with degeneration of the organ of Corti, spiral ganglion, stria vascularis in the cochlea, and vestibular ganglion in the labyrinth.|
|Amino Acid Change||Leucine changed to Arginine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted sequence gene model|
AA Change: L618R
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Phenotypic Category||behavior/neurological, nervous system|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Live Mice|
|Last Updated||05/13/2016 3:09 PM by Anne Murray|
|Record Created||08/03/2014 3:51 PM by Jeff SoRelle|
The coward phenotype was identified among G3 mice of the pedigree R0629, some of which exhibited head tossing, hyperactivity, and circling (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 65 mutations. The vestibular phenotype was linked to a mutation in Myo7a: a T to G transversion at base pair 98,085,466 (v38) on chromosome 7, or base pair 34,057 in the GenBank genomic region NC_000073. Linkage was found with a recessive model of inheritance (P = 7.884 x 10-6), wherein four affected mice were homozygous for the variant allele, and 17 unaffected mice were either heterozygous (n = 9) or homozygous (n = 7) for the reference allele (Figure 2). The mutation corresponds to residue 2,113 in the mRNA sequence NM_001256081 within exon 4 of 6 total exons.
The mutated nucleotide is indicated in red. The mutation results in a leucine (L) to arginine (R) substitution at position 618 (L618R) in the myosin VIIa (Myo7a) protein, and is strongly predicted by Polyphen-2 to cause loss of function (score = 1.00).
Myosins are divided into conventional (muscle myosins and myosins similar in structure and function to muscle myosins, all belonging to class II) and unconventional classes (myosins that do not resemble muscle myosins). Myo7a encodes myosin VIIa, a member of unconventional myosin family (1;2).
Myosin VIIa has a motor head domain, a regulatory neck domain, and a tail domain [(3;4); Figure 3]. The motor domain (amino acids 59-742) has an adenosine triphosphate (ATP)-binding site (amino acids 158-165) and an actin-binding site (amino acids 632-639). The motor domain facilitates the movement of myosin VIIa along actin filaments by utilizing the energy generated from the hydrolysis of ATP (5-7).
The myosin VIIa neck region has five IQ (isoleucine-glutamine) motifs (amino acids 743-765, 766-788, 791-811, 812-834, and 835-857) and a predicted coiled-coil (CC) region (amino acids 858-935). IQ motifs are α-helical structures that often mediate the binding of myosins to calmodulin, to members of the EF-hand family of calcium-binding proteins, or to myosin light chains [(8;9); reviewed in (10;11)]. IQ repeats 1, 2, and 4 of myosin VIIa promote the association of myosin VIIa with calmodulin (8;12;13); IQ repeats 3 and 5 may be associated with calmodulin-like proteins (3). The CC domain of myosin VIIa promotes the homodimerization (3;14).
Within the tail region of myosin VIIa are two myosin tail homology 4 (MyTH4) domains (amino acids 1017-1253 and 1747-1896), two band 4.1/ezrin/radixin/moesin (FERM)-like domains (amino acids 1254-1469 and 1898-2115), and a Src homology 3 (SH3) domain (amino acids 1606-1671) (3;4;14;15). The tail region of myosin VIIa interacts with vesicle-associated proteins (e.g., Slac2-c/MyRIP) indicating that it might regulate the cargo transport function of myosin VIIa (16-18). MyTH4 domains are proposed to function in microtubule and/or actin binding (19). FERM domains are often found in membrane-associated proteins and mediate the interaction of the FERM-containing proteins with the cytoplasmic domains of integral membrane proteins and/or they function as a mediator between the cell membrane and actin cytoskeleton (20-22). The FERM domains of myosin VIIa link myosin VIIa to other cytoskeletal proteins (2) and facilitate the association of myosin VIIa with melanosomes in the retinal pigment epithelium (RPE) (5). SH3 domains function in recognizing and binding proline-rich sequences (23) and are often found in proteins that function in synaptic vesicle endocytosis (24) and/or those that facilitate the proper localization of proteins (25). The MyTH4-FERM-SH3 (MFS) region of mouse myosin VIIa (amino acids 965-1649) has been crystallized [Figure 4; PDB:3PVL; (15)]. The MFS region exhibited a Y-shaped architecture whereby the MyTH4 domain packed with the F1 lobe of the FERM domain and the F1, F2, and F3 lobes of the FERM domain formed a cloverleaf configuration (15). The SH3 domain coupled to the F3 lobe via a short α-helix (15); the α-helix packed with the βB/βA/βE β-sheet of the SH3 domain to leave the canonical SH3 target-recognition pocket open. The MyTH4 domain consisted of a 10 α-helix bundle. The six central α helices (α2 and α5-α9) of the MyTH4 domain are highly conserved among proteins that contain MyTH4 domains and assembles into a right-handed superhelical core (15). The α9/α10 loop and α10 are also highly conserved among proteins that contain MyTH4 domains; α1, α3, and α4 are more divergent. The α9/α10 loop and α10 cap one end of the six-helix MyTH4 core and contact the F1 lobe of the FERM domain (15).
Myo7a encodes several alternatively spliced isoforms (3;4;26). The two primary isoforms of Myo7a are the canonical sequence and a shorter isoform that encodes a protein that differs from canonical myosin VIIa at amino acid 1171, where it diverges and ends 32 amino acids later in a stop codon (4).
The coward mutation (Leu618Arg) is within the motor head domain of myosin VIIa and preceeds the actin-binding motif.
MYO7A is expressed in adult human kidney and liver, the RPE, the photoreceptor cells of the retina, the embryonic cochlear and vestibular neuroepithelia, and developing olfactory receptor sensory neurons (3;6;27). Within the photoreceptor cells, myosin VIIa is localized in the inner segments and the base of the outer segments as well as in the synaptic region (28;29).
In the mouse, Myo7a is expressed in the retina, cochlea, kidney, and liver (6). At embryonic day (E) 9, the myosin VIIa protein is first observed in the optic vesicle (30). By E10, myosin VIIa is expressed in the olfactory epithelium and liver (30). At E12, expression is observed in the RPE, choroid plexus, adrenal gland, and tongue (30). At E13, expression is observed in the testis and anterior pituitary (30). In the mouse inner ear, myosin VIIa is strongly expressed in the sensory epithelia of the vestibular system (i.e., the saccular and utricular maculae and the three cristae) from as early as E14.5 (31). At E15, expression of myosin VIIa is noted in the small intestine, kidney, and hair follicles of the vibrissae (30). Within these tissues, myosin VIIa was only expressed in epithelial cell types (i.e., cell types that have microvilli or cilia) (30). In 16.5-day old mouse embryos, the cochlear and vestibular sensory hair cells of the inner ear as well as the epithelial cells of the small intestine, hepatocytes, and choroidal plexus expressed Myo7a (3;31). In the adult mouse, the myosin VIIa protein is expressed in the inner and outer hair cells of the cochlea, the apical region of RPE cells, testis, brain, ear, lung, and kidney (4;5;14;27). Within the hair cells of the inner ear, myosin VIIa localizes to the entire length of the stereocilia, the cuticular plate, and the pericuticular necklace (32).
Both primary Myo7a isoforms were highly expressed in the testis, while the shorter transcript was less abundant than canonical Myo7a (4). In the mouse, the shorter isoform was not detected in either the retina or the cochlea (4).
Myosins are actin-based molecular motors that generate mechanical force using the energy generated from the hydrolysis of ATP. Myosins function in organelle and vesicle movement, cytokinesis, phagocytosis, signal transduction, cellular movement, membrane trafficking, regulation of ion channels, and muscle contraction (33). Several unconventional myosins are essential for stereocilia development and/or maintenance including Myo6 (see the record for mayday circler), Myo15 (see the record for parker), and myosin VIIa (1). Mutations in Myo6, Myo15, or Myo7a result in stereocilia fusion, short stereocilia, and disorganized stereocilia, respectively (31;34;35). For more information about the general functions of myosins see mayday circler (Myo6), new gray (Myo5a), and parker (Myo15a).
Each hair cell in the inner ear is comprised of a bundle of up to 300 stereocilia that project from the apical cell surface (36;37); each stereocilium is filled with up to 1000 polarized and cross-linked actin filaments [Figure 5; (38)]. The stereocilia are organized in a staircase pattern and held together by extracellular lateral projections (side-links). Deflection of the hair bundle results in gating of transducer channels at the tips of the stereocilia and subsequent modulation of the cell membrane potential that converts the sound-evoked mechanical stimulus into an electrical signal (i.e., mechano-electrical transduction) (37;39). For more information about proteins involved in the maintenance and function of the hair cells of the inner ear please see the records for dee dee, squirm, and parker.
In the inner ear, myosin VIIa controls hair bundle morphogenesis, organization, and polarity (31;40) as well as the elongation of the stereocilia (41). Myosin VIIa functions in anchoring and holding membrane-bound elements to the actin core of the stereocilium as well as for normal gating of the transducer channels in the hair cells upon sustained deflection of the hair bundle (40;42;43).
Myosin VIIa, harmonin, cadherin 23 (Cdh23; see the record for dee dee), protocadherin 15 (Pcdh15; see the record for squirm), and Sans are all Usher syndrome 1 (USH1)-associated proteins. The USH1 proteins form a network of complexes within the stereocilia of hair cells (44). Mutations in any of the USH1 proteins results in hair cell stereocilia morphological defects. Myosin VIIa applies tension forces on hair bundle transient lateral links while in complex with Cdh23 and harmonin (40;42). In Myo7a mutant mice, harmonin is absent from the disorganized hair bundles indicating that myosin VIIa is required for harmonin transport along the actin core of the stereocilia during development (44). Myosin VIIa and Pcdh15 cooperate to regulate hair bundle development and function; in Myo7a-deficient mice, Pcdh15 is mislocalized (45). Myosin VIIa also interacts with twinfilin-2, an actin-binding protein that inhibits actin polymerization at the barbed end of the filament (46;47). Twinfilin-2 localizes to the tips of shorter stereocilia within the hair bundle (46). The myosin VIIa-twinfilin interaction is proposed to regulate stereocilia length within the hair bundle staircase (46). In hair cells from Myo7a knockout (Myo7a-/-) mice, whirlin, a protein that functions in stereocilia elongation, was abnormally persistently localized to the tip (41).
In the synaptic terminals of the photoreceptor cells of the retina, myosin VIIa colocalizes with Cdh23, Pcdh15, and harmonin. The myosin VIIa/Cdh23/Pcdh15/harmonin complex in the photoreceptor synapse is proposed to have a role in the structural and functional organization of the synaptic junction (48). Myosin VIIa regulates the transport of opsin (see the record for Bemr3) from the inner segment to the outer segment in photoreceptor cells (49), the phagocytosis of shed outer segment discs by the RPE (50), and melanosome localization to the apical processes of the RPE (51). Myosin VIIa is primarily required for the transport of phagosomes into the RPE cell body where they can then fuse with lysosomes (50). Phagocytosis of photoreceptor discs by the RPE is essential for photoreceptor cell viability; defects in this process may contribute to the progressive blindness observed in patients with MYO7A mutations (50). In the retina, myosin VIIa also interacts with the small GTPase Rab27 (see the record for concrete) that binds melanosomes via the linker protein Slac2-c/MyRIP (52;53). Myosin VIIa is required for the light-dependent translocation of the isomerohydrolase RPE65 to the central region of the RPE cells, a process necessary for the regulation of the visual retinoid cycle (54).
Mutations in MYO7A are linked to autosomal dominant deafness (DNFA11;OMIM: 601317; (55;56)), recessive deafness (DFNB2; OMIM: 600060; (57;58)), and Usher Syndrome type 1B (USH1B; OMIM: 276900; (3;4;6;26;59). DNFA11 is nonsyndromic, progressive neurosensory hearing loss; some patients exhibit mild vestibular symptoms (60). DFNB2 patients exhibit a variable onset of nonsyndromic neurosensory deafness and can also have vertigo (61;62). Patients with USH1B exhibit audiovestibular and visual defects including congenital sensorineural hearing loss, vestibular dysfunction, and retinitis pigmentosa leading to blindness (3).
Mutant Myo7a mice exhibit disturbances in stereocilia structure leading to varying loss of hearing and/or vestibular phenotypes. Several of these are described in more detail, below. In Myo7a816SB (MGI:2155423) mice, stereocilia grow and form normal graded stereocilia bundles, but the bundles become progressively disorganized (31). The electrophysiological responses of the mice were normal, but some hair cell depolarization occurred in spite of the bundle disorganization (31). Myo7aewaso (Ile487Asn; MGI:5487402) mice had hearing loss by 4 weeks of age along with vestibular dysfunction (i.e., hyperactivity and circling) (63). The Myo7aewaso mice exhibited hair cell degeneration at the basal cochlear region by 8 weeks of age with collapse of the organ of Corti (63). As early as postnatal day 5 (P5), Myo7aewaso mice exhibited abnormal inner hair cell bundle morphology at the basal level (63). By 2 weeks, inner hair cell bundles at the mid and basal levels of the cochlea were disorganized and some outer hair cell bundles were misoriented (63). The Myo7aewaso mice showed progressive inner and outer hair cell bundle degeneration so that by 8 weeks, outer hair bundles in the basal and mid levels of the cochlea are missing (63). Homozygous Myo7admbo2 (Phe947Ile; MGI:5487403) mice also had progressive hearing loss, but they did not exhibit vestibular dysfunction (63). The morphology of the sensory epithelium of the Myo7admbo2 mice was normal (63). The hair bundles in the Myo7admbo2 mice were affected in the apical level of the cochlea (63). As early as E18.5, the stereocilia bundle arrangement in Myo7aHdb (Ile178Phe; MGI:3511858) mice was abnormal: many inner ear hair stereocilia fused to form abnormally large stereocilia that subsequently degenerated (1). The organ of Corti of the Myo7aHdb mice had abnormal stereocilia bundle formation at the apex of the cochlea in that the stereocilia were all thin and of uniform length instead of in a staircase formation found in wild-type mice (1). As a result, the Myo7aHdb mice exhibited head bobbing and hyperactivity (1). Myo7aHdb mice showed elevated anxiety compared to wild-type mice in an open-field and elevated plus-maze (64). Shaker-1 mice (Arg502Pro; Myo7ash1, MGI:1856716) had normal early development of stereocilia bundles, but progressive disorganization and degeneration of the stereocilia, resulting in abnormal cochlear responses (1;31). The shaker-1 mice were deaf and exhibited vestibular dysfunction (i.e., head tossing, hyperactivity, and circling) (57;65). Myo7apolka (MGI:3708382) mice have an ENU-induced mutation within intron 42 that results in a splicing defect, coding of 33 aberrant amino acids, and coding of a premature stop codon within the C-terminal FERM domain (5). The Myo7apolka mice exhibited vestibular dysfunction (i.e., a circling behavior and poor performance in forced swim tests) as well as a lack of an acoustic startle response (5;66).
The coward mice exhibit vestibular defects similar to those observed for other Myo7a mutant mice with mutations in the motor domain including Myo7a816SB, Myo7aewaso, Myo7aHdb, and Myo7ash1 indicating that stereocilia formation and/or stereocilia bundle arrangement in the inner ear of the coward mice is disturbed. Hearing and retinal function in the coward mice have not been examined.
coward(F):5'- AACAGGCACTCTACAATCTTCAGGC -3'
coward(R):5'- TACCCCTTGACTGACCTTGGTGAC -3'
coward_seq(F):5'- caaggacaccgaggcac -3'
coward_seq(R):5'- GACTGACCTTGGTGACCTTCC -3'
Coward genotyping is performed by amplifying the region containing the mutation using PCR followed by sequencing of the amplified region to detect the nucleotide change. The following primers were used for PCR amplification:
Primers for PCR amplification
Coward(F): 5’- AACAGGCACTCTACAATCTTCAGGC-3’
Coward(R): 5’- TACCCCTTGACTGACCTTGGTGAC-3’
Primers for sequencing
Coward_seq(F): 5’- CAAGGACACCGAGGCAC-3’
1) 94° C 2:00
2) 94° C 0:30
3) 57° C 0:30
4) 72° C 1:00
5) repeat steps (2-4) 29x
6) 72° C 7:00
7) 4° C ¥
The following sequence of 541 nucleotides is amplified (Chr.7: 98085102-98085642, GRCm38; NC_000073):
aacaggcact ctacaatctt caggcatggt ctctggggag ttttcattct caaggacacc
gaggcacagg gcagtgtctg acttaggtac aaccgcccag ctgggagata gcaaagccaa
ggttaaggtg actgtggagc ccctatgccc tcagcaactt gacaagccct ttagtctcca
gagagaacaa ggctttcttt ccactgccca cctacctcat ccattttgcc ccctcccttc
ccaccctcca cccctgccca ccacatcccc tctgaggctc accatgggct tcttgaactc
attgggtttg atacaacgca caaagaaggg ctggcaggcg cccagtgtgc gcatcagcag
ctccagagac cgcttgaact ggctgctgag tgtaggcgag cgcttcctgg tctcggcacc
ctgtggcaga ggacagacag acagtgatgg gaggggccac ctcttccccc tcccaccctc
caacagctgt cctggaggga ggagagcacc agggaaggtc accaaggtca gtcaaggggt
PCR primer binding sites are underlined and the sequencing primer binding sites are underlined and italicized; the mutated nucleotide is shown in red text (A>C, Chr. (+) strand; T>G, sense strand).
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|Science Writers||Anne Murray|
|Authors||Jeff SoRelle, Zhe Chen, William McAlpine, Dylan Fortman|
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