Article

Basic helix-loop-helix transcription factor NEUROG1 and schizophrenia: Effects on illness susceptibility, MRI brain morphometry and cognitive abilities

Department of Psychiatry, University of Iowa Carver College of Medicine, USA.
Schizophrenia Research (Impact Factor: 4.43). 10/2008; 106(2-3):192-9. DOI: 10.1016/j.schres.2008.08.009
Source: PubMed

ABSTRACT Transcription factors, including the basic helix-loop-helix (bHLH) family, regulate numerous genes and play vital roles in controlling gene expression. Consequently, transcription factor mutations can lead to phenotypic pleiotropy, and may be a candidate mechanism underlying the complex genetics and heterogeneous phenotype of schizophrenia. Neurogenin1 (NEUROG1; a.k.a. Ngn1 or Neurod3), a bHLH transcription factor encoded on a known schizophrenia linkage region in 5q31.1, induces glutamatergic and suppresses GABAergic neuronal differentiation during embryonic neurodevelopment. The goal of this study is to investigate NEUROG1 effects on schizophrenia risk and on phenotypic features of schizophrenia. We tested 392 patients with schizophrenia or schizoaffective disorder and 226 healthy normal volunteers for association with NEUROG1. Major alleles on two NEUROG1-associated SNPs (rs2344484-C-allele and rs8192558-G-allele) were significantly more prevalent among patients (p<or=.0018). Approximately 80% of the sample also underwent high-resolution, multi-spectral magnetic resonance brain imaging and standardized neuropsychological assessment. There were significant rs2344484 genotype main effects on total cerebral gray matter (GM) and temporal GM volumes (p<or=.05). C-allele-carrier patients and healthy volunteers had smaller total cerebral GM and temporal GM volumes than their respective T-homozygous counterparts. rs2344484-C-allele was further associated with generalized cognitive deficits among schizophrenia patients but not in healthy volunteers. Our findings replicate previous association between NEUROG1 and schizophrenia. More importantly, this is the first study to examine brain morphological and neurocognitive correlates of NEUROG1. rs2344484-C-allele may affect NEUROG1's role in transcription regulation such that brain morphology and cognitive abilities are altered resulting in increased susceptibility to develop schizophrenia.

0 Bookmarks
 · 
60 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Proneural genes encode evolutionarily conserved basic-helix-loop-helix transcription factors. In Drosophila, proneural genes are required and sufficient to confer a neural identity onto naïve ectodermal cells, inducing delamination and subsequent neuronal differentiation. In vertebrates, proneural genes are expressed in cells that already have a neural identity, but they are still required and sufficient to initiate neurogenesis. In all organisms, proneural genes control neurogenesis by regulating Notch-mediated lateral inhibition and initiating the expression of downstream differentiation genes. The general mode of proneural gene function has thus been elucidated. However, the regulatory mechanisms that spatially and temporally control proneural gene function are only beginning to be deciphered. Understanding how proneural gene function is regulated is essential, as aberrant proneural gene expression has recently been linked to a variety of human diseases-ranging from cancer to neuropsychiatric illnesses and diabetes. Recent insights into proneural gene function in development and disease are highlighted herein.
    Current Topics in Developmental Biology 01/2014; 110C:75-127. DOI:10.1016/B978-0-12-405943-6.00002-6 · 4.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The production of neurons, astrocytes and oligodendrocytes is regulated by a group of transcription factors, which determine cell fates and specify subtype identities in the nervous system. Here we focus on profiling the distinct roles of Neurogenin (Ngn or Neurog) family members during the neuronal development. Ngn proteins are tightly regulated to be expressed at defined times and positions of different progenitor cell pools. In addition to their well-elucidated proneural function, Ngn proteins play various critical roles to specify or maintain cell fate and regulate neurite outgrowth and targeting in the central nervous system. Finally, Ngns have been associated with neuronal disorders. Therefore understanding the function and regulation of Ngns will not only improve the understanding of the molecular mechanism underlying the development of nervous system, but may also provide insight into neuronal disease.
    Archives of Biochemistry and Biophysics 06/2014; 558. DOI:10.1016/j.abb.2014.05.028 · 3.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Structural brain abnormalities have been extensively investigated as potential endophenotypes of schizophrenia. Apart from enlarged ventricles and whole brain volume reductions, no other consistently replicated brain morphometric abnormalities have emerged from these studies. The differential effect of genetic variants on brain morphometry could be a major source of variability underlying such inconsistent findings. Schizophrenia is a polygenic disorder, wherein the complex interplay between common risk variants of small effect, rare risk alleles of large effect as well as epigenetic interactions confer vulnerability and mediate the final expression of the clinical phenotype. A comprehensive understanding of the effect of risk genes on brain morphometry is essential for linking the structural endophenotype/s that can be linked with the genetic diathesis for development of schizophrenia. We systematically reviewed published literature to examine the effect of genes mediating neurodevelopment and brain signalling on brain morphometry. A majority of polymorphisms of the above genes was shown to be associated with whole brain and regional volumetric reductions; but importantly, many genes showed mixed effects, i.e., both volume reductions and increases. Modelling such complex interactions of the large number of risk genes on brain volume in vivo poses considerable practical challenges in having adequate sample sizes as well as imaging data for reliable quantification. Therefore, it is recommended that the field should move beyond association studies of the morphometric effect of single or limited number of gene polymorphisms in clinical populations to modelling the complex epistatic and epigenetic interactions in silico or using animal and cellular models.
    Neurology Psychiatry and Brain Research 03/2015; DOI:10.1016/j.npbr.2014.11.003 · 0.13 Impact Factor

Preview

Download
0 Downloads
Available from