A point mutation at the calreticulin gene core promoter conserved sequence in a case of schizophrenia

Aghajani, Ali; Rahimi, Alireza; Fadai, Farbod; Ebrahimi, Ahmad; Najmabadi, Hossein; Ohadi, Mina

doi:10.1002/ajmg.b.30300

Cited by 18 publications

(10 citation statements)

References 11 publications

(10 reference statements)

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“…Interestingly, the existence of a possible role played by ER stress and UPR modulators in the pathogenesis of clinically relevant conditions such as bipolar disorder and schizophrenia is further highlighted by two other genetic association studies, where mutations or SNPs have been identified in the genes encoding the ER-resident chaperones calreticulin and GRP94/GP96 (Aghajani et al, 2006; Kakiuchi et al, 2007). Also, PDI variants (Kwok et al, 2013), UBQLN2 and p62/ SQSTM1 mutations participate in ALS development (Deng et al, 2011; Teyssou et al, 2013).…”

Section: Impaired Upr Machinery As a Cause Of Neurodegenerationmentioning

confidence: 99%

The Endoplasmic Reticulum Unfolded Protein Response in Neurodegenerative Disorders and Its Potential Therapeutic Significance

Remondelli¹,

Renna²

2017

Front. Mol. Neurosci.

139

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In eukaryotic cells, the endoplasmic reticulum (ER) is the cell compartment involved in secretory protein translocation and quality control of secretory protein folding. Different conditions can alter ER function, resulting in the accumulation of unfolded or misfolded proteins within the ER lumen. Such a condition, known as ER stress, elicits an integrated adaptive response known as the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway. Conversely, in prolonged cell stress or insufficient adaptive response, UPR signaling causes cell death. ER dysfunctions are involved and contribute to neuronal degeneration in several human diseases, including Alzheimer, Parkinson and Huntington disease and amyotrophic lateral sclerosis. The correlations between ER stress and its signal transduction pathway known as the UPR with neuropathological changes are well established. In addition, much evidence suggests that genetic or pharmacological modulation of UPR could represent an effective strategy for minimizing the progressive neuronal loss in neurodegenerative diseases. Here, we review recent results describing the main cellular mechanisms linking ER stress and UPR to neurodegeneration. Furthermore, we provide an up-to-date panoramic view of the currently pursued strategies for ameliorating the toxic effects of protein unfolding in disease by targeting the ER UPR pathway.

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Section: Impaired Upr Machinery As a Cause Of Neurodegenerationmentioning

confidence: 99%

The Endoplasmic Reticulum Unfolded Protein Response in Neurodegenerative Disorders and Its Potential Therapeutic Significance

Remondelli¹,

Renna²

2017

Front. Mol. Neurosci.

139

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“…With a lifetime prevalence of ∼0.32% [Perälä et al, 2007], schizoaffective disorder is considered as one of the most common psychiatric illnesses. We have recently reported a G > C point mutation located at position −48 within the core promoter of the calreticulin gene in a family case of paranoid schizophrenia also diagnosed with bipolar disorder [Aghajani et al, 2006]. The functionality of the mutation was studied in neural cortical cells, which revealed an aberrant expression of the gene in the mutant versus the wild‐type sequence [Nunes et al, 2008].…”

Section: Primer Sequences Used For the Screening Of The Human Calretimentioning

confidence: 99%

“…Our first report of mutation in the core promoter of the gene [Aghajani et al, 2006], in association with the whole‐genome linkage and functional data implicated the calreticulin gene as a promising candidate for the causation of the disease. Because none of the known genes located at the 19p13.2 interval have been linked to psychiatric disorders, calreticulin emerges as the best candidate gene whose dysregulation may trigger schizoaffective disorder.…”

Section: Primer Sequences Used For the Screening Of The Human Calretimentioning

confidence: 99%

Novel mutations in the calreticulin gene core promoter and coding sequence in schizoaffective disorder

Nabi¹,

Mirabzadeh²,

Feizzadeh³

et al. 2010

American J of Med Genetics Pt B

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We have recently reported the first case of mutation in the core promoter sequence of the human calreticulin gene in a family case of schizoaffective disorder. Remarkably, this gene coincides with a region of suggested linkage at 19p13.2, identified in a whole genome scan [Hamshere et al. (2005); Arch Gen Psychiatry 62;1081-1088]. The identified mutation was located at the conserved position -48 from the transcription start site, and was shown to be of functional effect, resulting in the aberrant expression of the gene. Following screening of the gene in 60 independent cases of schizoaffective disorder, we report novel germ-line mutations at positions -205 C > T and the conserved exon 5 (c: 682 C > T, pro228ser) in two unrelated cases of schizoaffective disorder. These mutations were disease-specific, and as for the -48 G > C mutation, neither was detected in a control population of 370 individuals, indicating a contribution of 3.17% in this sample series. To our knowledge, this is the first instance of disease-specific mutations in schizoaffective disorder, which warrants systematic screening of the regulatory and coding regions of the calreticulin gene in this disorder.

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“…Pharmacological evidence of the therapeutic effect of CALR (Bodmer and Bonilla 2008;Bown et al 2002;Chen et al 2000;Kim et al 2005;Shao et al 2006;Yuan et al 2001) in psychosis, further strengthen the role of CALR as a promising candidate in the causation of major psychiatric disorders. We have previously reported cases of psychosisassociated promoter mutations with estimated frequencies of less than 0.0007 in the general population (Aghajani et al 2006;Farokhashtiani et al 2011;Olad Nabi et al 2010). Those mutations occurred at positions -220 (rs138452745), -205 (rs556992558), and -48 (CR061331).…”

Section: Introductionmentioning

confidence: 97%

Decreased gene expression activity as a result of a mutation in the calreticulin gene promoter in a family case of schizoaffective disorder

et al. 2015

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Accumulating evidence of population association studies support the hypothesis that the high heritability of major psychiatric disorders is a combination of relatively common alleles of modest effect, and rare alleles some with relatively larger effects. We have previously reported low frequency mutations in the proximal promoter of the human calreticulin (CALR) gene that co-occur with the spectrum of major psychiatric disorders. One of those mutations at -205C>T (rs556992558) was detected in an isolate case of schizoaffective disorder. In the current study, the functional implication of mutation -205T is studied in the human neuronal cell lines LAN-5, BE(2)-C and HEK-293. In contrast with other mutations in the promoter region which increase gene expression activity, the -205T mutation significantly decreased gene expression in those cell lines in comparison with the wild-type -205C nucleotide (p < 0.000001, p < 0.0005, and p < 0.017, respectively). Treatment of the cell lines with the mood-stabilizing drug, valproic acid (VPA) resulted in differential gene expression activity in the mutant -205T versus the wild-type -205C construct. VPA increased gene expression activity in both constructs, while a significantly higher expression activity was observed in the mutant construct (p < 0.01), indicative of the creation of a positive effector binding site for VPA as a result of the -205T mutation. We conclude that deviation from normalcy in the level of CALR in either direction is associated with major psychiatric disorders.

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A point mutation at the calreticulin gene core promoter conserved sequence in a case of schizophrenia

Cited by 18 publications

References 11 publications

The Endoplasmic Reticulum Unfolded Protein Response in Neurodegenerative Disorders and Its Potential Therapeutic Significance

The Endoplasmic Reticulum Unfolded Protein Response in Neurodegenerative Disorders and Its Potential Therapeutic Significance

Novel mutations in the calreticulin gene core promoter and coding sequence in schizoaffective disorder

Decreased gene expression activity as a result of a mutation in the calreticulin gene promoter in a family case of schizoaffective disorder

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