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.
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Several highly selective markers for RCs have been implicated as risk factors for neuropsychiatric disease, including netrin G1 (NTNG1) for Rett syndrome and neurotrypsin (PRSS12) for mental retardation.
“For example, several highly selective markers for RCs have been implicated as risk factors for neuropsychiatric disease, including netrin G1 (NTNG1) for Rett syndrome47 and neurotrypsin (PRSS12) for mental retardation48.”
From Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type (2018) · cites this paper as [47]
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- Authors
- Borg, I., Freude, K., Kübart, S., Hoffmann, K., Menzel, C., Laccone, F., Firth, H., Ferguson-Smith, M. A., Tommerup, N., Ropers, H.-H., Sargan, D., & Kalscheuer, V. M.
- Affiliations
- Max Planck Institute for Molecular Genetics (DE)
- University of Göttingen (DE)
- University of Cambridge (GB)
- University of Copenhagen (DK)
- Corresponding author
- Kalscheuer, Vera M
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2005-05-04
- Volume
- 13
- Issue
- 8
- Pages
- 921-927
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- OpenAlex
- W1985389254
- Cited by
- 95
- References
- 16
- Citations by year
- 2024: 2 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 6 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 8
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- National Research Foundation
- Danmarks Grundforskningsfond
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Rett syndrome, NTNG1, chromosome 1, chromosome 7, de novo translocation, gene disruption, alternative splicing, splice variants, glycosylphosphatidylinositol anchor, candidate disease genes, central nervous system
- MeSH terms
- Netrins, Base Sequence, Child, Preschool, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 7, Female, Humans, Infant, Molecular Sequence Data, Nerve Tissue Proteins, Translocation, Genetic, Rett Syndrome, Protein Serine-Threonine Kinases, In Situ Hybridization, Fluorescence, Methyl-CpG-Binding Protein 2
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