Disease relevance of Myo15

• Endbulbs of Held in 7-month old, deaf sh2 mice exhibited fewer synaptic vesicles in the presynaptic ending, the loss of intercellular cisternae, and a hypertrophy of associated postsynaptic densities [1].
• Mutations of the unconventional myosins genes encoding myosin VI, myosin VIIA and myosin XV cause hearing loss and thus these motor proteins perform fundamental functions in the auditory system [2].

High impact information on Myo15

• This histopathology suggests that Myo15 is necessary for actin organization in the hair cells of the cochlea [3].
• Genetic mapping has refined sh2 to a 0.6-cM interval of chromosome 11 [4].
• On the basis of conserved synteny, mouse deafness mutations shaker-2 (sh2) and sh2J are proposed as models of DFNB3 [4].
• The pirouette (pi) mouse also exhibits deafness and an inner ear pathology resembling that of Myo15 mutant mice and thus may be functionally related to Myo15 [5].
• These data suggest that the function of Myo15 is distinct from that of Myo6, Myo7a or pi in development and/or maintenance of stereocilia [5].

Biological context of Myo15

• The shaker 2(J) lesion, in contrast, is a 14.7 kb deletion that removes the last six exons from the 3"-terminus of the Myo15 transcript [6].
• The shaker 2 allele is a previously described missense mutation of a highly conserved residue in the motor domain of myosin XV [6].
• These mice carry a point mutation on chromosome 11, affecting myosin 15 and producing abnormally short stereocilia in hair cells of the inner ear [1].
• Mutant alleles of a third unconventional myosin, myosin XV, are associated with nonsyndromic, recessive, congenital deafness DFNB3 on human chromosome 17p11.2 and deafness in shaker2 (Myo15(sh2)) mice [2].
• Transgene correction maintains normal cochlear structure and function in 6-month-old Myo15a mutant mice [7].

Anatomical context of Myo15

• The motor and tail regions of myosin XV are critical for normal structure and function of auditory and vestibular hair cells [6].
• In outer and inner hair cells, myosin XV protein is detectable in the cell body and stereocilia [2].
• These results identified potential cellular pathways associated with myosin XV defects, and age-associated molecular events that are likely to be involved in maturation of the cochlea and auditory function [8].
• The insertion of a bacterial artificial chromosome (BAC) transgene containing the Myo15a gene into sh2/sh2 zygotes confers hearing capability and abolishes the circling behavior in 1-month-old transgenic animals [7].

Other interactions of Myo15

• Vibrator (gene symbol vb), an autosomal recessive mutation, occurred spontaneously in the DBA/2J strain of mice, was rescued by a single cross to C57BL/6J and subsequent brother X sister mating, and has been mapped near shaker-2 (sh-2) and vestigial tail (vt) on chromosome 11 [9].

Analytical, diagnostic and therapeutic context of Myo15

• In addition, excess Myo15a expression has no physiologically significant protective or deleterious effects on hearing of normal mice, suggesting that the dosage of Myo15a may not be problematic for gene therapy [7].

References