Abstract
We have identified a girl with characteristic features of Rett syndrome (RTT) who carries a de novo balanced translocation involving chromosomes 1 and 7. Both breakpoints were mapped by fluorescence in situ hybridization with selected genomic clones from the regions of interest. Southern blot hybridisations, utilizing probes derived from breakpoint spanning BACs, detected several aberrant fragments specific for the patient. Sequence analysis of the cloned junction fragment indicated that on chromosome 1 the predominantly brain-expressed Netrin G1 (NTNG1) gene is disrupted, whereas on chromosome 7 there was no indication for a truncated gene. The chromosome 1 breakpoint lies within the 3′ part of NTNG1 and affects alternatively spliced transcripts, suggesting that the phenotype in this patient is the result of disturbed NTNG1 expression. In silico translation of the NTNG1 splice variants predicted protein isoforms with different C-termini: one membrane bound through a glycosylphosphatidylinositol anchor and the other soluble. The membrane-bound protein isoform would be affected by the breakpoint, whereas the soluble form would remain intact. Our results suggest that the central nervous system is sensitive to NTNG1 expression levels and that NTNG1 is a novel candidate disease gene for RTT.
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Acknowledgements
We are grateful to the patients and their families. We thank Patricia CM O'Brien (CVBS, Cambridge) for performing chromosome sorting. This work was supported by the German Human Genome Program (01KW99087), the National Genome Research Network (01GR0105) and a scholarship to IB from the Association of Commonwealth Universities. Wilhelm Johannsen Centre for Functional Genome Research is established by the Danish National Research Foundation.
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Borg, I., Freude, K., Kübart, S. et al. Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome. Eur J Hum Genet 13, 921–927 (2005). https://doi.org/10.1038/sj.ejhg.5201429
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DOI: https://doi.org/10.1038/sj.ejhg.5201429
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