Functional Studies of "Deafness Genes" Essential for Hearing

National Institute On Deafness And Other Communication Disorders

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Abstract

The statement below is a brief summary of a few ongoing projects in the Laboratory of Molecular Genetics, NIDCD/NIH. One project being completed is on the function of MYO15 in stereocilia development and long term maintenance of the hair bundle (Moreland et al 2023 Nature Communications, under revision). We are also continuing to pursue studies of mouse models of human deafness genes that have been identified in the LMG. At least two of the three major isoforms of TRIOBP (TRIOBP-4 and TRIOBP-5, identified from our previous published studies of human nonsyndromic autosomal recessive deafness) are necessary for normal hair cell stereocilia rootlet formation and the maintenance of rootlets in the adult organ of Corti. Stereocilia rootlets provide bundle stiffness necessary for the detection of sound and, paradoxically, also flexibility at stereocilia pivot points, which is the topic of a manuscript presently being crafted by Inna Belyantseva in collaboration with several extramural laboratories in the United States. The function of TRIOBP-1, the third major TRIOBP alternative isoform if any, in the auditory system has not been reported and is being examined using a floxed exon 1 of mouse Triobp. Exon 1 of Triobp is unique to the Triobp-1 isoform (i.e. not used in transcripts of Triobp-4 and Triobp-5 splice isoforms). Similar experimental strategies are being used to study in mouse the functions of genes necessary for hearing in human that are identified from genetic analyses of large families segregating deafness. These genes presently include LRP2, MAP3K1 and ADAMTS.