Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome

TY - JOUR

T1 - Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome

AU - Borg, Isabella

AU - Freude, Kristine

AU - Kübart, Sabine

AU - Hoffmann, Kirsten

AU - Menzel, Corinna

AU - Laccone, Franco

AU - Firth, Helen

AU - Ferguson-Smith, Malcolm A

AU - Tommerup, Niels

AU - Ropers, Hans-Hilger

AU - Sargan, David

AU - Kalscheuer, Vera M

N1 - Keywords: Base Sequence; Child, Preschool; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 7; Female; Humans; In Situ Hybridization, Fluorescence; Infant; Methyl-CpG-Binding Protein 2; Molecular Sequence Data; Nerve Tissue Proteins; Protein-Serine-Threonine Kinases; Rett Syndrome; Translocation, Genetic

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

U2 - 10.1038/sj.ejhg.5201429

DO - 10.1038/sj.ejhg.5201429

M3 - Journal article

C2 - 15870826

SN - 1018-4813

VL - 13

SP - 921

EP - 927

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 8

ER -