Disruption of the neuronal PAS3 gene in a family affected with schizophrenia

Abstract

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.

The myelin-pathogenesis puzzle in schizophrenia: a literature review

“…It appears that the brain transcription factor neuronal PAS domain protein 3 (NPAS3) is affected by the translocation and thus has a possible role in the manifestation of psychotic symptoms. 61,72 For other genes on this chromosome, V-AKT murine thymoma viral oncogene homolog 1 (AKT1), an arbitrator of neuronal survival in the developing brain, is a promising vulnerability gene. 14 …”

NPAS3 Demonstrates Features of a Tumor Suppressive Role in Driving the Progression of Astrocytomas

“…14 In a spatiotemporally controlled manner in the cerebellum, nuclear expression has also been identified in basket cells and in Bergmann's glia, with some cytoplasmic staining evident in the internal granule layer of neurons. 14 After initial cloning of the NPAS3 gene, 13 the objective of the present study was to investigate the role of this gene in diseases in human beings. Previous studies have suggested a potential role of NPAS3 in congenital neurobehavioral and neurodevelopmental anomalies.…”

Neurogenic hypothesis and psychiatric disorders

“…Neuronal PAS domain-containing protein 3 (NPAS3) is another worth noting gene with susceptibility of schizophrenia [85]. NPAS3 is a basic helix-loop-helix transcription factor which was discovered in a family that suffered from schizophrenia [85].…”

“…NPAS3 is a basic helix-loop-helix transcription factor which was discovered in a family that suffered from schizophrenia [85]. Transgenic mice with NPAS3 mutation showed a behavioral phenotype with reduced memory, impaired social recognition and impaired sensorimotor gating [86], which are also characteristics of schizophrenic patients.…”

“…Though some other controversial results have also shown, these results have given the possible relationship between the morphological changes of the amygdala and the pathophysiologic development of autism. Mercadante et al [99] [110,111] Growth factors: 1) Brain-derived neurotrophic factor (BDNF) [31] 2) Vascular endothelial growth factor (VEGF) [41] 3) Insulin-like growth factor 1 (IGF1) [41] Neurotransmitters: 1) GABA [36] 2) Serotonin [37] 3) Glutamate/NMDA receptor [38] 4) Dopamine and acetylcholine [39] -Decrease in number of Ki-67 +ve cells in schizophrenia patients [26] Intracellular molecules: 1) Disrupted in Schizophrenia 1 (DISC1) [75] 2) Neuronal PAS domain protein 3 (NPAS3) [85] 3) Neuregulin 1 (NRG1) [ [99,103] have further suggested that the new immature-neurons newly produced in the amygdala may be helpful in increasing the ability to learn from new experiences via modulation of the gamma-aminobutyric acid (GABA) as patients with autism were found to have alteration on the GABAergic system. However, further investigations are needed as this is a new etiologic hypothesis of autism.…”