Disruption of the neuronal PAS3 gene in a family affected with schizophrenia
Open accessAbstract
Schizophrenia and its subtypes are part of a complex brain disorder with multiple postulated aetiologies. There is evidence that this common disease is genetically heterogeneous, with many loci involved. In this report, we describe a mother and daughter affected with schizophrenia, who are carriers of a t(9;14)(q34;q13) chromosome. By mapping on flow sorted aberrant chromosomes isolated from lymphoblast cell lines, both subjects were found to have a translocation breakpoint junction between the markers D14S730 and D14S70, a 683 kb interval on chromosome 14q13. This interval was found to contain the neuronal PAS3 gene (NPAS3), by annotating the genomic sequence for ESTs and performing RACE and cDNA library screenings. The NPAS3 gene was characterised with respect to the genomic structure, human expression profile, and protein cellular localisation to gain insight into gene function. The translocation breakpoint junction lies within the third intron of NPAS3, resulting in the disruption of the coding potential. The fact that the bHLH and PAS domains are disrupted from the remaining parts of the encoded protein suggests that the DNA binding and dimerisation functions of this protein are destroyed. The daughter (proband), who is more severely affected, has an additional microdeletion in the second intron of NPAS3. On chromosome 9q34, the translocation breakpoint junction was defined between D9S752 and D9S972 and no genes were found to be disrupted. We propose that haploinsufficiency of NPAS3 contributes to the cause of mental illness in this family.
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Disruption of NPAS3 by a reciprocal translocation in chromosome 14q13 was reported in a family with intellectual disability and schizophrenia.
“Disruption of NPAS3 by a reciprocal translocation in chromosome 14q13 was reported in a family with intellectual disability and schizophrenia (Kamnasaran et al. 2003; Pickard et al. 2005)”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Kamnasaran et al. 2003
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Research works printed but not linked: 1
- Malloy MP, Cox DW, Kamnasaran D, Ferguson-Smith MA, Picard BS, Porteus DJ, Blackwood DR, Muir WJ. Mapping chromosome breakpoints using fibre-FISH in a family with a translocation t(9;14)(q34q13) chromosome and psychiatric illness. 8th World Congress on Psychiatric Genetics. Abstract P327 Am J Med Genet 2000;96:551-552..
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“In addition, family and association studies have identified NPAS3 as a candidate gene for schizophrenia in families (Kamnasaran et al. 2003; Pickard et al. 2005, 2006) and association studies (Pickard et al. 2009; Huang et al. 2010).”
Background
- Authors
- Kamnasaran, D., Muir, W. J., Ferguson-Smith, M. A., & Cox, D. W.
- Affiliations
- University of Alberta (CA)
- Western General Hospital (GB)
- University of Cambridge (GB)
- Corresponding author
- Cox, D W
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2003-05
- Volume
- 40
- Issue
- 5
- Pages
- 325-332
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC1735455
- OpenAlex
- W2158490907
- Cited by
- 146
- References
- 32
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 1 · 2019: 4 · 2018: 11 · 2017: 4 · 2016: 7 · 2015: 7 · 2014: 4 · 2013: 6 · 2012: 8
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- March of Dimes Foundation
- University of Alberta
- Fondation pour la Recherche Médicale
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- schizophrenia, NPAS3, chromosome 9q34, microdeletion, haploinsufficiency, bHLH domain, PAS domain, family studies, gene disruption
- MeSH terms
- Peroxins, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 9, Female, Fungal Proteins, Humans, Introns, Membrane Proteins, Molecular Sequence Data, Neurons, RNA, Messenger, Schizophrenia, Translocation, Genetic, Sequence Deletion, DNA, Complementary, ATP-Binding Cassette Transporters, Chromosome Breakage, Physical Chromosome Mapping, Gene Expression Profiling, Saccharomyces cerevisiae Proteins
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