title: A novel allele of myosin VIIa reveals a critical function for the C-terminal FERM domain for melanosome transport in retinal pigment epithelial cells.
abstract: Mutations in the head and tail domains of the motor protein myosin VIIA (MYO7A) cause deaf-blindness (Usher syndrome type 1B, USH1B) and nonsyndromic deafness (DFNB2, DFNA11). The head domain binds to F-actin and serves as the MYO7A motor domain, but little is known about the function of the tail domain. In a genetic screen, we have identified polka mice, which carry a mutation (c.5742 + 5G > A) that affects splicing of the MYO7A transcript and truncates the MYO7A tail domain at the C-terminal FERM domain. In the inner ear, expression of the truncated MYO7A protein is severely reduced, leading to defects in hair cell development. In retinal pigment epithelial (RPE) cells, the truncated MYO7A protein is expressed at comparative levels to wild-type protein but fails to associate with and transport melanosomes. We conclude that the C-terminal FERM domain of MYO7A is critical for melanosome transport in RPE cells. Our findings also suggest that MYO7A mutations can lead to tissue-specific effects on protein levels, which may explain why some mutations in MYO7A lead to deafness without retinal impairment.
authors.affiliation: Department of Cell Biology, Institute for Childhood and Neglected Disease, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwander
authors.forename: Vanda
authors.initials: V
authors.lastname: Lopes
authors.forename: Anna
authors.initials: A
authors.lastname: Sczaniecka
authors.forename: Daniel
authors.initials: D
authors.lastname: Gibbs
authors.forename: Concepcion
authors.initials: C
authors.lastname: Lillo
authors.forename: David
authors.initials: D
authors.lastname: Delano
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Tarantino
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Ulrich
authors.initials: U
authors.lastname: Müller
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001307:Auditory Perception / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics*; D020460:Melanosomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism*; D052245:Usher Syndromes / Q000235:genetics / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D009218:Myosins