Association of NPAS3 exonic variation with schizophrenia

Macintyre, Georgina; Alford, T. C.; Xiong, Lan; Rouleau, Guy A.; Tibbo, Philip G.; Cox, Diane W.

doi:10.1016/j.schres.2010.04.002

Cited by 43 publications

(41 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, no previous studies, including those by our group, 16,20 have yet demonstrated a strong link between NPAS3 with any congenital disease such as holoprosencephaly. The present study was initiated from a search for astrocytoma candidate genes using data derived from the Cancer Genome Project and pre-screenings of our panel of 433 surgically resected astrocytoma specimens.…”

Section: Discussionmentioning

confidence: 81%

“…Previous studies have suggested a potential role of NPAS3 in congenital neurobehavioral and neurodevelopmental anomalies. 12,13,19 However, no nonpolymorphic mutations have yet been identified in human subjects with isolated neurobehavioral deficits, 20 leading to the postulation that the neurobehavioral deficit documented in the original family 13 was not an isolated clinical phenomenon but perhaps a consequence of midline structural anatomical defects of the nervous system. 16 Furthermore, deletion of chromosome 14 with NPAS3 has been reported in numerous tumors including oligodendrogliomas, melanomas, and carcinomas of the breast, prostate gland, and urogenital tract, as compared with normal nonneoplastic tissues, 5,[21][22][23] but with yet to be characterized functional roles in these cancers.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Moreira

Kiehl

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Malignant astrocytomas, the most common primary brain tumors, are predominantly fatal. Improved treatments will require a better understanding of the biological features of high-grade astrocytomas. To better understand the role of neuronal PAS 3 (NPAS3) in diseases in human beings, it was investigated as a candidate for astrocytomagenesis based on the presence of aberrant protein expression in greater than 70% of a human astrocytoma panel (n ‫؍‬ 433) and most notably in surgically resected malignant lesions. In subsequent functional studies, it was concluded that NPAS3 exhibits features of a tumor-suppressor, which drives the progression of astrocytomas by modulating the cell cycle, proliferation, apoptosis, and cell migration/invasion and has a further influence on the viability of endothelial cells. Of clinical importance, absence of NPAS3 expression in glioblastomas was a significantly negative prognostic marker of survival. In addition, malignant astrocytomas lacking NPAS3 expression demonstrated loss of function mutations, which were associated with loss of heterozygosity. While overexpressed NPAS3 in malignant glioma cell lines significantly suppressed transformation, the converse decreased expression considerably induced more aggressive growth. In addition, knockdown NPAS3 expression in a human astrocyte cell line in concert with the human papillomavirus E6 and E7 oncogenes induced growth of malignant astrocytomas. In conclusion, NPAS3 drives the progression of human malignant astrocytomas as a tumor suppressor and is a negative prognostication marker for survival.

show abstract

Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

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

Moreira

Kiehl

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Furthermore, two genes (RGPD8 and ZC3H6) have protein domains with predicted functions (Golgi-targeted Ran GTPase-binding protein and zinc finger transcription factor, respectively) but no reported function in development. Additionally, genomic alterations in the NPAS3 gene have been associated with schizophrenia and mental retardation, but no NTDs were reported in these patients (99). In summary, we identified several de novo CNVs in patients with spina bifida that contain genes not previously implicated in neural tube closure.…”

Section: Analysis Of De Novo Cnvs Identifies Potential Genes That Maymentioning

confidence: 77%

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

Bassuk

Muthuswamy

Boland³

et al. 2012

Human Molecular Genetics

View full text Add to dashboard Cite

Neural tube defects (NTDs) are common birth defects of complex etiology. Family and population-based studies have confirmed a genetic component to NTDs. However, despite more than three decades of research, the genes involved in human NTDs remain largely unknown. We tested the hypothesis that rare copy number variants (CNVs), especially de novo germline CNVs, are a significant risk factor for NTDs. We used array-based comparative genomic hybridization (aCGH) to identify rare CNVs in 128 Caucasian and 61 Hispanic patients with non-syndromic lumbar-sacral myelomeningocele. We also performed aCGH analysis on the parents of affected individuals with rare CNVs where parental DNA was available (42 sets). Among the eight de novo CNVs that we identified, three generated copy number changes of entire genes. One large heterozygous deletion removed 27 genes, including PAX3, a known spina bifida-associated gene. A second CNV altered genes (PGPD8, ZC3H6) for which little is known regarding function or expression. A third heterozygous deletion removed GPC5 and part of GPC6, genes encoding glypicans. Glypicans are proteoglycans that modulate the activity of morphogens such as Sonic Hedgehog (SHH) and bone morphogenetic proteins (BMPs), both of which have been implicated in NTDs. Additionally, glypicans function in the planar cell polarity (PCP) pathway, and several PCP genes have been associated with NTDs. Here, we show that GPC5 orthologs are expressed in the neural tube, and that inhibiting their expression in frog and fish embryos results in NTDs. These results implicate GPC5 as a gene required for normal neural tube development.

show abstract

“…Later, Pickard et al (2009) could show that common genetic variation in the NPAS3 gene is associated with both schizophrenia and BPD. Furthermore, coding non-synonymous variants were identified and demonstrated to be associated with schizophrenia (Macintyre et al, 2010), which might well underlie the association of common, intronic variants (Dickson et al, 2010). Additionally, NPAS3 was identified in two GWAS to be associated with iloperidone response (Lavedan et al, 2009) and, interestingly, BPD .…”

Section: Npas3mentioning

confidence: 99%

Cross-Disorder Analysis of Bipolar Risk Genes: Further Evidence of DGKH as a Risk Gene for Bipolar Disorder, but also Unipolar Depression and Adult ADHD

Weber

Kittel‐Schneider

Gessner

et al. 2011

Neuropsychopharmacol

View full text Add to dashboard Cite

Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n=387) or adult attention-deficit/hyperactivity disorder (aADHD; n=535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65-243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH.

show abstract

Association of NPAS3 exonic variation with schizophrenia

Cited by 43 publications

References 51 publications

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

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

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

Cross-Disorder Analysis of Bipolar Risk Genes: Further Evidence of DGKH as a Risk Gene for Bipolar Disorder, but also Unipolar Depression and Adult ADHD

Contact Info

Product

Resources

About