Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot–Marie–Tooth disease, is directly regulated by the transcription factor SOX10

Mutations in SOX10, a transcription modulator crucial in the development of the enteric nervous system(ENS), melanocytes and glial cells, are found in Shah- Waardenburg syndrome(WS4), a neurocristopathythat associates intestinal aganglionosis, pigmentation defects and sensorineural deafness. Expression of MITF and RET, two genes that play important roles during melanocyte and ENS development, respectively, are controlled by SOX10. The observation that some WS4 patients present with myelinationdefects of the central and peripheral nervous systems correlates with the recent finding that P 0 , a major component of the peripheral myelin, is another transcriptional target of SOX10. These phenotypic features suggest that SOX10could regulate expression of other genes involved in the myelinationprocess as well. Thus, we tested the ability of SOX10to regulate expression of MBP, PMP22 and Connexin 32, three major proteins of the peripheral myelin. Our study shows that this factor, in synergy with EGR2, strongly activates Cx32 expression in vitro by directly binding to its promoter. In agreement with this finding, SOX10and EGR2 mutants identified in patients with peripheral myelindefects fail to transactivate the Cx32 promoter. Moreover, we show that a mutation of the Cx32 promoter previously described in a patient with the X-linked form of Charcot-Marie-Tooth (CMTX) disease impairs SOX10function. In addition to providing new insights into the molecular mechanisms underlying some of the peripheral myelindefects observed in CMTX disease, these results further extend the spectrum of genes that are regulated by SOX10.