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Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis


Neural progenitor proliferation and migration influence brain size during neurogenesis. We report an autosomal recessive microcephaly syndrome cosegregating with a homozygous balanced translocation between chromosomes 3p and 10q, and we show that a position effect at the breakpoint on chromosome 3 silences the eomesodermin transcript (EOMES), also known as T-box-brain2 (TBR2). Together with the expression pattern of EOMES in the developing human brain, our data suggest that EOMES is involved in neuronal division and/or migration. Thus, mutations in genes encoding not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes.

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Figure 1: Segregation, genetic and fine physical mapping of the disease locus.
Figure 2: Silencing of the translocated EOMES locus and normal EOMES expression in the developing human brain.


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The authors thank the microcephaly syndrome family for their participation. We thank Z. Al-Houssaini, N. Bahi-Buisson, C. Chirol, M. Clément-Ziza, N. Moussok, A. Pelet, S. Romana, C. Schatz and M. Vekemans for their assistance. This study was funded by INSERM, Agence Nationale de la Recherche and the Fondation pour le Recherche Médicale.

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Correspondence to Stanislas Lyonnet.

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Supplementary information

Supplementary Fig. 1

Clinical features. (PDF 387 kb)

Supplementary Fig. 2

FISH analyses of BACs RP11-9A14 (chromosome 3p) and RP11-102H24 (chromosome 10q). (PDF 139 kb)

Supplementary Fig. 3

Sequencing of the junction fragments on 3p24 and 10q22. (PDF 426 kb)

Supplementary Table 1

BAC probes encompassing the 3p and 10q translocation breakpoint. (PDF 65 kb)

Supplementary Table 2

Methods for RT-PCR analysis of candidate genes on chromosome 3p and 10q. (PDF 108 kb)

Supplementary Methods (PDF 123 kb)

Supplementary Note (PDF 79 kb)

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Baala, L., Briault, S., Etchevers, H. et al. Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis. Nat Genet 39, 454–456 (2007).

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