TRPML3 and hearing loss in the varitint-waddler mouse.

TRPML3 (also known as mucolipin-3, MCOLN3) belongs to the small family of TRPML ion channel proteins. The mammalian Trpml3 gene encodes a protein of 553 amino acids with short amino and carboxy termini and a transient receptor potential motif spanning from the third to the sixth trans membrane domain. Dominant mutant alleles of Trpml3 cause hearing loss, circling behaviour, pigmentation defects and embryonic lethality in the varitint-waddler (Va) mouse. In the inner ear these mutations cause a reduction or loss of endocochlear potentials, compound action potentials, and auditory-evoked brain stem responses. The hearing phenotype is associated with defects in the cochlea that include disorganization and fusion of stereocilia, distortions at the apical and distal regions of inner and outer hair cells, and loss of pigmented intermediate cells in the stria vascularis. In hair cells the TRPML3 protein is targeted to cytoplasmic vesicles and to the plasma membrane of stereocilia. Both the sub-cellular localization of TRPML3 and the mutant phenotype suggest that TRPML3 is critical for stereocilia bundle formation during development and may function during endocytosis or exocytosis.