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.

日本語要旨:

遺伝性の複合型神経堤症候群PCWHのトランスジェニックモデルマウスを初めて作成し、その病態機序を明らかにした。PCWHは、SOX10遺伝子の特定の変異によって生ずる先天性大脳白質形成不全症を含む様々な症状を呈する稀少疾患であるが、これまでモデル動物が存在せず、十分な病態解析がなされていなかった。本論文では、初めてPCWHのモデルマウスを作成し、、胎生期から成体に及ぶまでの詳細な組織学的解析を行うことにより、SOX10変異が優性に相加的効果をもたらす表現型にもたらすことを示した。