title: Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH.
abstract: 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 thoroughly understood. To determine the pathogenesis of PCWH, we have established a transgenic mouse model. A known 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 transgene. Within the nervous systems, transgenic mice revealed a delay in the incorporation of Schwann cells in the sciatic nerve and the terminal differentiation of oligodendrocytes in the spinal cord. Transgenic mice also showed defects in 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 for mutant SOX10. By uncoupling the effects of gain-of-function and haploinsufficiency in vivo, we have demonstrated that the effect of a PCWH-causing SOX10 mutation is solely pathogenic in each SOX10-expressing cellular lineage in a dosage-dependent manner. In both the peripheral and central nervous systems, the primary consequence of SOX10 mutations is hypomyelination. The complex neurological phenotypes in PCWH patients likely result from a combination of haploinsufficiency and additive dominant effect.
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Ogawahigashi, 4-1-1, Kodaira, Tokyo 187-8502, Japan; Department of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Electronic address: c57bl6j@excite.co.jp.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Ogawahigashi, 4-1-1, Kodaira, Tokyo 187-8502, Japan. Electronic address: inouenok@yahoo.co.jp.
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoue
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Electronic address: yinn3@ncnp.go.jp.
authors.forename: Yukiko U
authors.initials: YU
authors.lastname: Inoue
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Ogawahigashi, 4-1-1, Kodaira, Tokyo 187-8502, Japan. Electronic address: ramukana@ncnp.go.jp.
authors.forename: Shoko
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Developmental Disorders, National Institute of Mental Health, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Electronic address: yoshiki_0430@yahoo.co.jp.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Department of Developmental Disorders, National Institute of Mental Health, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Electronic address: inagaki@ncnp.go.jp.
authors.forename: Masumi
authors.initials: M
authors.lastname: Inagaki
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Ogawahigashi, 4-1-1, Kodaira, Tokyo 187-8502, Japan. Electronic address: galoistaka@gmail.com.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohkubo
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Electronic address: asami@ncnp.go.jp.
authors.forename: Junko
authors.initials: J
authors.lastname: Asami
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan; Division of Morphological Neuroscience, Gifu University Graduate School of Medicine, 1-1 Yanagito, Gifu, Gifu 501-1194, Japan. Electronic address: y_tera@gifu-u.ac.jp.
authors.forename: Youhei W
authors.initials: YW
authors.lastname: Terakawa
authors.affiliation: Department of Neurochemistry, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Electronic address: kohsaka@ncnp.go.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kohsaka
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Ogawahigashi, 4-1-1, Kodaira, Tokyo 187-8502, Japan. Electronic address: goto@ncnp.go.jp.
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Department of Neurochemistry, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan; Department of Biochemistry and Biophysics, Graduate School of Health Care Sciences, TMDU, 1-5-45 Yushima, Bunkyo-ku, 113-8510 Tokyo, Japan. Electronic address: c.akazawa.bb@tmd.ac.jp.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Akazawa
authors.affiliation: Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Electronic address: tinoue@ncnp.go.jp.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Ogawahigashi, 4-1-1, Kodaira, Tokyo 187-8502, Japan. Electronic address: kinoue@ncnp.go.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000648:ultrastructure; D003337:Corpus Callosum / Q000648:ultrastructure; D003711:Demyelinating Diseases / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005799:Genes, Dominant; D057895:Haploinsufficiency; D006627:Hirschsprung Disease / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009432:Neural Crest / Q000002:abnormalities; D010641:Phenotype; D055757:SOXE Transcription Factors / Q000235:genetics*; D012583:Schwann Cells / Q000473:pathology; D012584:Sciatic Nerve / Q000648:ultrastructure; D014849:Waardenburg Syndrome / Q000196:embryology / Q000235:genetics* / Q000473:pathology
chemical_list: C527923:SOX10 protein, human; D055757:SOXE Transcription Factors
keywords: BAC transgenic mouse; Mutant SOX10; PCWH