A Missense Mutation Within the Fork-head Domain of the Forkhead Box G1 Gene (FOXG1) Affects its Nuclear Localization

作者：Le Guen Tangui; Fichou Yann; Nectoux Juliette; Bahi Buisson Nadia; Rivier Francois; Boddaert Nathalie; Diebold Bertrand; Heron Delphine; Chelly Jamel; Bienvenu Thierry^*

来源：Human Mutation, 2011, 32(2): E2026-E2035.

DOI：10.1002/humu.21422

• FOXG1
• Rett syndrome
• Microcephaly
• Encephalopathy
• Nuclear speckles

The forkhead box G1 (FOXG1) gene has recently been associated with the congenital variant of Rett syndrome, and so far 17 mutations have been reported. We screened the coding region in 150 patients affected by postnatal microcephaly, and identified two mutations: the c.326C>T (p.P109L) substitution inherited from the healthy father; and the de novo c.730C>T transition, which induces the p.R244C mutation within the DNA-binding forkhead domain. This latter mutation is carried by an 8-year-old girl, who presented a phenotype reminiscent of the congenital variant of Rett syndrome. Immunofluorescence analysis of the wild-type protein revealed a homogeneous nuclear staining excluding the nucleoli, while the p.R244C mutant showed abnormal nuclear foci in a large proportion of cells, suggesting that its mislocalization may reduce and/or impair target recognition. Interestingly, this missense mutation results in a mislocalization of FoxG1 to specific nuclear foci referred to as nuclear speckles, and affects the cyclin-dependent kinase inhibitor p21 CDKN1A expression. Because CDKL5, which is involved in the early-onset variant of Rett syndrome, is also located in these speckles, we suggest that disregulation of the dynamic behaviour of nuclear speckles may functionally link these two proteins, which are both involved in atypical forms of Rett syndrome.

• 出版日期2011-2