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Myosin VII (Usher syndrome)

Updated 11/2/03

Usher syndrome affects four in every 100,000 live births.  Some forms of the disease are known to be caused by mutations in the myosin VIIa gene (reviewed, Eudy & Sumegi, 1999; Maniak, 2001).  Patients suffer combined hearing and eye function impairments.  In the eye, the condition gets progressively worse, but the course of the disease is dependent on the nature of the mutation.
Myosin VII  A dimeric protein complex like many myosins Connected through the coiled coil domain.  The repeated MyTH4 and FERM domains bind a number of proteins (see table 1).

Myosin VIIa is a plus (barbed) end directed motor (Inoue & Ikebe, 2003). Loss of myosin VIIa function leads to the failure of cilia to form.  Usher syndrome is usually inherited as a recessive trait meaning that as long as an individual has a correct copy of the gene, then he/she will be OK.  However, this is a mutation that is dominant and that is found within the coiled-coil domain.  Such domains in other proteins and in fact other myosins are dimerization domains and so it is suspected that a “bad” copy may disrupt the function of good copies of the protein by interference with their structure.  Usher patient show abnormal nasal ciliary cells, sperm as well as photorecpetor cell damage  (see below).  Mutations in the mouse homologue give rise to the shaker-1 phenotype, which is characterized by hyperactivity, head-tossing and circling behaviour due to vestibular and cochlear  dysfunction.  A number of possible explanations have been suggested for the involvement of myosin VIIa in the ear and eye.  The protein is localised to the cilium connecting the outer-segment to the inner segment (the cell body).  The waist formed by the cilium may be to allow two very different membrane domains to coexist in the same cell, in which case, the function of myosin VII may well be to facilitate this by actively removing inappropriate proteins.  It has also been suggested that the function is to transport opsin to the outer segment from the inner segment where it is made.  A very recent study in Dictyostelium finds that this organism (despite neither hearing nor seeing) expressed a myosin VII homolog (Titus, 1999).  When this gene was knocked out the amoeba could not phagocytose.  This amoeba expresses an abundance of myosin family members particularly the myosin I group.  Many of these have produced phenotype including a reduction in phagocytosis but none as marked as this myosin VII knockout.  So it seems that the function of this particular myosin in Dictyostelium is phagocytosis.  There has been an almost uncanny conservation in the cytoskeletal proteins right across the phyla from amoeba to humans and this infers that the function of myosin VII in humans may also be phagocytosis.  This makes sense in the biological context of the ear (lots of phagocytosis at the roots of the cilia) and in the eye.  The outer segment of the eye is continually shed, so as to turnover the structures damaged by the constant exposure to light

Yet another function that Myosin VII appears to have is a role in the dynamics of cell adhesion (Tuxworth et al, 2001).  Again using the Dictyostelium mutant (lacking the functional myosin VII homolog), were discovered to be deficient in cell adhesion.  Myosin VII in these cells is normally localised to the leading edge in motile cells and to the tips of extending filopods.  Myosin VII in stereo cilia is located at the tip link connection and so may be playing a similar role in stabilizing the connection through the cell membrane to the tip link in concert with the cadherin family member described earlier.  

Lateral link- cytoskeleton  connection - Vezatin

This is a trans-membranous protein identified by the yeast two-hybrid system using the FERM domain of myosin VII as bait (Kussel- Andermann, et al, 2001).  Vezatin therefore binds myosin VII by the FERM region and also to the cadherin/a-catenein complex. Sensory cell specific cadherins family member bind to a lateral-link across the extra-cellular space.  This link may also bind vezatin although there is no information at present. The C-terminus of cadherin binds a complex of cytoskeletal proteins so that forces are transmitted from one cell to the other via a lateral link. The attachment of Myosin VII to the complex may allow the lateral link to be transported in the plane of the membrane


Protein Function Reference
Calmodulin A calcium-binding protein which acts here as a light chain, five binds each myosin VII heavy chain Todorov et al, 2001
Harmonin b Binds to a complex that connects the lateral link connector to the actin cytoskeleton through myosin VIIa Boeda et al, 2002
MAP2b Microtubule Associated Protein  Todorov et al, 2001
MyRIP Rab27 interacting protein that binds myosin VIIa El-Amraoui et al, 2002
RIa cAMP dependent protein kinase (PKA) Kussel-Andermann et al, 2000
Vezatin Lateral link connector Kussel-Andermann et al, 2001
Table 1  Myosin VII binding proteins


Cuevas, J. M., Espinós, C., Millán, J. M., Sánchez, F., Trujillo, M. J., García-Sandoval, B., Ayuso, C., Nájera, C. & Beneyto, M. (1998) Detection of a novel Cys628STOP mutation of the myosin VIIa in Usher syndrome type Ib., Mol.Cell.Probes. 12, 417-420.

El-Amraoui, A., Schonn, J.-S., Kussel-Andermann, P., Blanchard, S., Desnos, C., Henry, J.-P., Wolfrum, U., Darchen, F. & Petit, C. (2002) MyRIP, a novel Rab effector, enables myosin VIIa recruitment to retinal melasomes. EMBO reports. 3, 463-470.

Farber, D. B. & Danciger, M. (1997) Identification of genes causing photoreceptor degenerations leading to blindness. Curr.Op.Neurobiol. 7, 666-673.

Gillespie, P. G. (1997) Multiple myosin motors and mechanoelectrical transduction by hair cells. Biol.Bull. 192, 186-190.

Hasson, T. & Mooseker, M. S. (1997) The growing family of myosin motors and their role in neurons and sensory cells. Curr. Op. Neorobiol. 7, 615-623.

Inoue, A. & Ikebe, M. (2003) Characterization of the Motor Activity of Mammalian Myosin VIIA J. Biol. Chem. 278, 5478-5487.

Kussel-Andermann, P., El-Amraoui, A., Safieddine, S., Nouaille, S., Perfettini, I., Lecuit, M., Cossart, P., Wolfrum, U. & Petit, C. (2000) Vezatin, a novel transmembrane protein, bridges myosin VIIA to the cadherin-catenins complex. EMBO J. 19, 6020-6029.

Kussel-Andermann, P., El-Amraoui, A., Safieddine, S., Hardelin, J.-P., Nouaille, S., Camonis, J. & Petit, C. (2000) Unconventional Myosin VIIA Is a Novel A-kinase-anchoring Protein. J. Biol. Chem. 275, 29654-29659.

Liu, X., Vansant, G., Udovichenko, I. P., Wolfrum, U. & Williams, D. S. (1997) Myosin VIIa, the product of the Usher 1B syndrome gene, is concentrated in the connecting cilia of photoreceptor cells. Cell Mot.Ctyoskeleton. 37, 240-252.

Liu, X.-Z., Walsh, J., Mburu, P., Kendrick-Jones, J., Cope, J. T. V., Steel, K. P. & Brown, S. D. M. (1997) Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nature genetics. 16, 188-190.

Liu, X.-Z., Walsh, J., Tamagawa, Y., Kitamura, K., Nishizawa, M., Steel, K. P. & Brown, S. D. M. (1997) Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIa gene. Nature genetics. 17, 268-269.

Maniak, M. (2001) Cell adhesion: Ushering in a new understanding of myosin VII. Current Biology. 11, R315-R317.

Mburu, P., Liu, X.-Z., Walsh, J., Saw, D., Cope, J. T. V., Gibson, F., Kendrick-Jones, J., Steel, K. P. & Brown, S. D. M. (1997) Mutation analysis of the mouse myosin VIIA deafness gene. Genes and Function. 1, 191-203.

Self, T., Mahony, M., Fleming, J., Walsh, J., Brown, S. D. M. & Steel, K. P. (1998) Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear har cells. Development. 125, 557-566.

Titus, M. A. (1999) A class VII unconventional myosin is required for phagocytosis. Curr.Biol. 9, 1297-1303.

Todorov, P. T., Hardisty, R. E. & Brown, S. D. M. (2001) Myosin VIIa is specifically associated with calmodulin and microtubule-associated protein-2B (MAP-2B). Biochem. J. 354, 267-274.

Tuxworth, R. I., Weber, I., Wessels, D., Addicks, G. C., Soll, D. R., Gerisch, G. & Titus, M. A. (2001) A role for myosin VII in dynamic cell adhesion.  Curr.Biol. 11, 318-329.

Weil, D., Blanchard, S., Kaplan, J., Guilford, P., Gibson, F., Walsh, J., Mburu, P., Varela, A., Levilliers, J., Weston, M. D., Kelley, P. M., Kimberling, W. J., Wagenaar, M., Levi-Acobas, F., Larget-Piet, D., Munnich, A., Steel, K. P., Brown, S. D. M. & Petit, C. (1995) Defective myosin VIIa gene responsible for usher syndrome type 1b. Nature. 374, 60-61.

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