title: Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome.
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.
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Isabella
authors.initials: I
authors.lastname: Borg
authors.forename: Kristine
authors.initials: K
authors.lastname: Freude
authors.forename: Sabine
authors.initials: S
authors.lastname: Kübart
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Corinna
authors.initials: C
authors.lastname: Menzel
authors.forename: Franco
authors.initials: F
authors.lastname: Laccone
authors.forename: Helen
authors.initials: H
authors.lastname: Firth
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Ferguson-Smith
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: David
authors.initials: D
authors.lastname: Sargan
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1; D002897:Chromosomes, Human, Pair 7; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D051783:Methyl-CpG-Binding Protein 2 / Q000032:analysis / Q000235:genetics; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D000075385:Netrins; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D000075385:Netrins; C413653:netrin-G1; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human