Abstract du Pr H Arnheiter, MD, Scientific emeritus NIH Bethesda USA, en visite au C3M Nice

Syndromic deafness and the role of the transcription factor MITF

The microphthalmia-associated transcription factor MITF has emerged a jack-of-all-trades able to coordinate many aspects of developmental and cell biology by controlling the expression of a great variety of target genes. Its key function is in regulating neural crest-derived melanocytes and their malignant derivatives. In mammals, melanocytes play a particularly interesting role in hearing. During embryonic development, a subset of their precursors lodge in the inner ear where they integrate as intermediate cells in the so-called stria vascularis. When MITF is rendered non-functional by mutations, strial melanocytes are missing, which in turn leads to a change in the ionic composition of the endolymph and an inability of auditory hair cells to release neurotransmitters and stimulate the auditory nerve. In humans, the resulting disorder is called Waardenburg Syndrome (WS) IIa, which is usually characterized by a combination of congenital deafness with pigmentation defects in skin, hair, and iris. It is normally inherited in an autosomal dominant fashion but may show considerable phenotypic variations within families. I will discuss some of the WS IIa mutations and demonstrate how an inconspicuous intronic nucleotide transversion in mice can lead to the complete absence of MITF function.