Additive toxicity of SOX10 mutation underlies a complex neurological phenotype of PCWH. K. Inoue1, Y. Ito1,2, N. Inoue1, Y. U. Inoue3, S. Nakamura1, Y. Matsuda4, M. Inagaki4, T. Ohkubo1, J. Asami3, Y. W. Terakawa3, S. Kohsaka5, Y. Goto1, C. Akazawa5,6, T. Inoue3 1) Dept MR & BD Res, Natl Inst Neurosci, NCNP, Kodaira, Tokyo, Japan; 2) Dept Molecular Neuroscience, Med Res Inst, Tokyo Med & Dent Univ., Tokyo, Japan; 3) Dept. Biochemistry & Cellular Biology, Natl Inst Neurosci, NCNP Tokyo, Japan; 4) Dept. Developmental Disorders, Natl Inst Neurosci, NCNP Tokyo, Japan; 5) Dept. Neurochemistry, Natl Inst Neurosci, NCNP Tokyo, Japan; 6) Dept Biochemistry & Biophysics, Grad School of Health Care Sciences, Tokyo Med & Dent Univ., Tokyo, Japan.

   Distinct classes of SOX10 mutations result in peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, collectively known as PCWH. Meanwhile, SOX10 haploinsufficiency caused by allelic loss-of-function mutations leads to a milder non-neurological disorder, Waardenburg-Hirschsprung disease. The cellular pathogenesis of more complex PCWH phenotypes in vivo has not been elucidated until now. Here we determined the pathogenesis of PCWH by constructing a transgenic mouse model. A PCWH-causing SOX10 mutation, c.1400del12, was introduced into mouse Sox10-expressing cells by means of bacterial artificial chromosome (BAC) transgenesis. By crossing the multiple transgenic lines, we examined the effects produced by various copy numbers of the mutant SOX10 transgene. In the nervous systems, transgenic mice revealed delay in integration of Schwann cells in the sciatic nerve and terminal differentiation of oligodendrocytes in the spinal cord. Transgenic mice also showed defects of melanocytes presenting as neurosensory deafness and abnormal skin pigmentation, and a loss of the enteric nervous system. Phenotypes in each lineage were more severe in mice carrying higher copy numbers, suggesting a gene dosage effect of toxic mutant SOX10. By uncoupling the effects of gain-on-function and haploinsufficiency in vivo, we have demonstrated that the effect of a PCWH-causing SOX10 mutation is solely toxic in all SOX10-expressing cells in dosage-dependent manner. In both peripheral and central nervous systems, primary consequence of SOX10 mutations is hypomyelination. The complex neurological phenotypes in PCWH patients likely result from a combination of haploinsufficiency and additive dominant toxicity.

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