| 1 | Am. J. Med. Genet. 2001 Aug 105: 529-33 |
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| PMID | 11496370 |
| Title | Association study of a promoter polymorphism of UFD1L gene with schizophrenia. |
| Abstract | schizophrenia or schizoaffective disorders are often found in patients affected by DiGeorge/velo-cardio-facial syndrome (DGS/VCFS) as a result of hemizygosity of chromosome 22q11.2. We evaluated the UFD1L gene, mapping within the DGS/VCFS region, as a potential candidate for schizophrenia susceptibility. UFD1L encodes for the ubiquitin fusion degradation 1 protein, which is expressed in the medial telencephalon during mouse development. Using case control, simplex families (trios), and functional studies, we provided evidence for association between schizophrenia and a single nucleotide functional polymorphism, -277A/G, located within the noncoding region upstream the first exon of the UFD1L gene. The results are supportive of UFD1L involvement in the neurodevelopmental origin of schizophrenia and contribute in delineating etiological and pathogenetic mechanism of the schizophrenia subtype related to 22q11.2 deletion syndrome. |
| SCZ Keywords | schizophrenia |
| 2 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Oct 147B: 1076-9 |
| PMID | 18270977 |
| Title | A family- and population-based study of the UFD1L gene for schizophrenia. |
| Abstract | The present work was undertaken to investigate the association of the UFD1L locus with schizophrenia among 304 Chinese family trios of Han descent. We detected four single nucleotide polymorphisms (SNPs) in the 5'-end region of the UFD1L gene. The transmission disequilibrium test (TDT) revealed allelic associations for rs5746744 (chi(2) = 8.02, P = 0.005) and rs1547931 (chi(2) = 7.18, P = 0.007), but failed to replicate disease association for rs5992403 present in the promoter region, which was initially found in Italian and Canadian samples. The allelic association for rs5746744 and rs1547931 was replicated with independently recruited case-control samples. The 2-SNP haplotype analysis showed an association for the rs5992403-rs5746744 haplotypes (chi(2) = 18.92, df = 3, P = 0.0003), the rs5746744-rs1547931 haplotypes (chi(2) = 11.06, df = 3, P = 0.011) and the rs1547931-rs2238769 haplotypes (chi(2) = 18.88, df = 3, P = 0.0003). The 4-SNP haplotype analysis also showed strong association with illness (chi(2) = 29.54, df = 9, P = 0.0005) but there were more than one individual haplotypes with a low frequency excessively non-transmitted. The four SNPs tested were not located in the same LD block among the Chinese population. This study raises the possibility that a disease-resistant variant may be carried by two or more haplotypes at the UFD1L locus due to frequent recombination during meiosis. |
| SCZ Keywords | schizophrenia |
| 3 | J Psychiatr Res 2010 Nov 44: 1113-5 |
| PMID | 20471029 |
| Title | The UFD1L rs5992403 polymorphism is associated with age at onset of schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia |
| 4 | PLoS ONE 2012 -1 7: e33473 |
| PMID | 22457764 |
| Title | Functional gene-expression analysis shows involvement of schizophrenia-relevant pathways in patients with 22q11 deletion syndrome. |
| Abstract | 22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's) of 8 22q11DS patients and 8 age- and gender-matched controls, to (1) investigate the expression levels of 22q11 genes and (2) to investigate whether 22q11 genes participate in functional genetic networks relevant to schizophrenia. Functional relationships between genes differentially expressed in patients (as identified by Locally Adaptive Statistical procedure (LAP) or satisfying p<0.05 and fold-change >1.5) were investigated with the Ingenuity Pathways Analysis (IPA). 14 samples (7 patients, 7 controls) passed quality controls. LAP identified 29 deregulated genes. Pathway analysis showed 262 transcripts differentially expressed between patients and controls. Functional pathways most disturbed were cell death, cell morphology, cellular assembly and organization, and cell-to-cell signaling. In addition, 10 canonical pathways were identified, among which the signal pathways for Natural Killer-cells, neurotrophin/Trk, neuregulin, axonal guidance, and Huntington's disease. Our findings support the use of 22q11DS as a research model for schizophrenia. We identified decreased expression of several genes (among which COMT, UFD1L, PCQAP, and GNB1L) previously linked to schizophrenia as well as involvement of signaling pathways relevant to schizophrenia, of which Neurotrophin/Trk and neuregulin signaling seems to be especially notable. |
| SCZ Keywords | schizophrenia |
| 5 | Psychiatry Res 2013 Aug 209: 110-3 |
| PMID | 23623450 |
| Title | Polymorphisms in schizophrenia candidate gene UFD1L may contribute to cognitive deficits. |
| Abstract | We aimed to investigate UFD1L polymorphisms in schizophrenia and in relation to cognition. A total of 299 cases and 363 controls were genotyped, and 130 patients completed nine neuropsychological tests. We found that rs5992403 AA-genotype carriers showed lower scores on the set-shifting task. Therefore, UFD1L may participate in the core cognitive deficits observed in schizophrenia. |
| SCZ Keywords | schizophrenia |
| 6 | J. Biol. Chem. 2015 Sep 290: 23240-53 |
| PMID | 26221035 |
| Title | Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome. |
| Abstract | The congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5-3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of ?30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of ?-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1?, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype. |
| SCZ Keywords | schizophrenia |
| 7 | World J. Biol. Psychiatry 2015 Jun -1: 1-6 |
| PMID | 26089098 |
| Title | Gene expression analysis in blood of ultra-high risk subjects compared to first-episode of psychosis patients and controls. |
| Abstract | This study aimed to investigate peripheral blood gene expression in ultra-high-risk subjects (UHR) compared to first-episode psychosis individuals (FEP) and healthy controls (HC). We enrolled 22 UHR, 66 FEP and 67 HC and investigated the expression of 12 genes using Taqman assays. We used the Univariate General Linear Model, as well as Bonferroni correction for multiple comparisons. We found that UFD1L (ubiquitin fusion degradation 1 like (yeast)) gene was upregulated in UHR group compared to HC and FEP (P = 3.44 × 10(-6) ; P = 9.41 × 10(-6)). MBP (myelin basic protein) was downregulated in UHR compared to FEP (P = 6.07 × 10(-6)). DISC1 (disrupted in schizophrenia 1) was also upregulated in UHR compared to FEP but lost statistical significance when corrected for age. These genes are directly related to neurodevelopmental processes and have been associated to schizophrenia. Recent findings described that DISC1 overexpression can disrupt MBP expression, thus, we think that these alterations in UHR individuals could be associated with a common process. UFD1L showed a different pattern of expression only for UHR group, suggesting that they can be under an acute endoplasmatic reticulum stress, demanding elevated levels of Ufd1. Further studies can improve knowledge on disease progression and putative targets to preventive strategies. |
| SCZ Keywords | schizophrenia |