Human Molecular Genetics Advance Access originally published online on June 25, 2007
Human Molecular Genetics 2007 16(17):2097-2104; doi:10.1093/hmg/ddm157
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IKAP/hELP1 deficiency in the cerebrum of familial dysautonomia patients results in down regulation of genes involved in oligodendrocyte differentiation and in myelination
1 Department of Pediatrics, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel, 2 Genomic Data Analysis Unit of the Hebrew University Medical School, 3 Department of Human Molecular Genetics, Tel Aviv University Medical School, Ramat Aviv, Israel and 4 Department of Cellular Biochemistry and Human Genetics, The Hebrew University Medical School, Jerusalem, Israel
* To whom correspondence should be addressed. Tel: +972 26758172; Fax: +972 26415848; Email: razina{at}huji.ac.il
Received May 2, 2007; Revised June 19, 2007; Accepted June 19, 2007
The gene affected in the congenital neuropathy familial dysautonomia (FD) is IKBKAP that codes for the IKAP/hELP1 protein. Several different functions have been suggested for this protein, but none of them have been verified in vivo or shown to have some link with the FD phenotype. In an attempt to elucidate the involvement of IKAP/hELP1 in brain function, we searched for IKAP/hELP1 target genes associated with neuronal function. In a microarray expression analysis using RNA extracted from the cerebrum of two FD patients as well as sex and age matched controls, no genes were found to be upregulated in the FD cerebrum. However, 25 genes were downregulated more than 2-fold in the cerebrum of both the male FD child and female FD mature woman. Thirteen of them are known to be involved in oligodendrocyte development and myelin formation. The down regulation of all these genes was verified by real-time PCR. Four of these genes were also confirmed to be downregulated at the protein level. These results are statistically significant and have high biological relevance, since seven of the downregulated genes in the cerebrum of the FD patients were shown by others to be upregulated during oligodendrocyte differentiation in vitro. Our results therefore suggest that IKAP/hELP1 may play a role in oligodendrocyte differentiation and/or myelin formation.
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