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[P2.75]: Malformations of cortical development: Genomic analysis by high density microarrays in a large patient cohort
Author(s) -
Mancini G.M.,
Schot R.,
Poulton C.,
Kia S. Kheradmand,
Oegema R.,
Verheijen F.
Publication year - 2010
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2010.07.205
Subject(s) - dna microarray , cohort , computational biology , neuroscience , biology , medicine , genetics , gene , gene expression
SOX10 is a transcription factor that is essential for the neural crest development and the myelin formation both in the PNS and CNS. SOX10 mutations are associated with two distinct neurocristopathies, Waardenburg-Hirschsprung disease (WS4) and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease (PCWH), latter of which shows more complex and severe neurological phenotype. Clinical and molecular findings suggested that WS4 results form haploinsufficiency of SOX10, while PCWH is predicted to results from SOX10 acting as either dominant-negative or gain-of-function allele. Although model animals are available for WS4, no animal models for PCWH are currently present. To determine the molecular mechanisms for PCWH in vivo, we have founded BAC-transgenic mice (Tg) carrying a PCWH-causing mutant Sox10 construct. Tg showed abnormal motor coordination, circling behavior, hypopigmented coat color, perceptive deafness, and abnormal enlargement of colon. Microscopic examinations in nerve systems showed relatively normal migration and differentiation of oligodendrocyte and Schwann cells, but apparently delayed myelination in Tg mice. These findings suggested that the mutant Sox10 Tg mice mimic phenotypes observed in human patients with PCWH and thus serve as a model for PCWH.