Mitochondrial localization and function of a subset of 22q11 deletion syndrome candidate genes

Department of Cell and Molecular Physiology, The University of North Carolina School of Medicine, Chapel Hill, NC 27599-7545, USA.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 09/2008; 39(3):439-51. DOI: 10.1016/j.mcn.2008.07.027
Source: PubMed


Six genes in the 1.5 Mb region of chromosome 22 deleted in DiGeorge/22q11 deletion syndrome-Mrpl40, Prodh, Slc25a1, Txnrd2, T10, and Zdhhc8-encode mitochondrial proteins. All six genes are expressed in the brain, and maximal expression coincides with peak forebrain synaptogenesis shortly after birth. Furthermore, their protein products are associated with brain mitochondria, including those in synaptic terminals. Among the six, only Zddhc8 influences mitochondria-regulated apoptosis when overexpressed, and appears to interact biochemically with established mitochondrial proteins. Zdhhc8 has an apparent interaction with Uqcrc1, a component of mitochondrial complex III. The two proteins are coincidently expressed in pre-synaptic processes; however, Zdhhc8 is more frequently seen in glutamatergic terminals. 22q11 deletion may alter metabolic properties of cortical mitochondria during early post-natal life, since expression complex III components, including Uqcrc1, is significantly increased at birth in a mouse model of 22q11 deletion, and declines to normal values in adulthood. Our results suggest that altered dosage of one, or several 22q11 mitochondrial genes, particularly during early post-natal cortical development, may disrupt neuronal metabolism or synaptic signaling.

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    • "In yeast, this protein has been shown to play a role in growth rate, mitochondrial protein folding, and mitochondrial function [34, 35]. In humans, the Mrpl40 gene is part of a chromosomal deletion of 22q11 in velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome [36, 37]. The remaining two proteins, cardiotrophin-like cytokine factor 1 (Clcf1) and HIV TAT specific factor 1 (Htatsf1), were identified in this and all three (30, 120, 240 minute) TCDD treatment data sets. "
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    ABSTRACT: The aryl-hydrocarbon receptor (AHR), a ligand activated PAS superfamily transcription factor, mediates most, if not all, of the toxicity induced upon exposure to various dioxins, dibenzofurans, and planar polyhalogenated biphenyls. While AHR-mediated gene regulation plays a central role in the toxic response to dioxin exposure, a comprehensive understanding of AHR biology remains elusive. AHR-mediated signaling starts in the cytoplasm, where the receptor can be found in a complex with the heat shock protein of 90 kDa (Hsp90) and the immunophilin-like protein, aryl-hydrocarbon receptor-interacting protein (AIP). The role these chaperones and other putative interactors of the AHR play in the toxic response is not known. To more comprehensively define the AHR-protein interaction network (AHR-PIN) and identify other potential pathways involved in the toxic response, a proteomic approach was undertaken. Using tandem affinity purification (TAP) and mass spectrometry we have identified several novel protein interactions with the AHR. These interactions physically link the AHR to proteins involved in the immune and cellular stress responses, gene regulation not mediated directly via the traditional AHR:ARNT heterodimer, and mitochondrial function. This new insight into the AHR signaling network identifies possible secondary signaling pathways involved in xenobiotic-induced toxicity.
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    • "Several studies showed that PAT is localized in the Golgi apparatus and vesicular compartment of neurons where the protein palmitoylation is its central function.99 Maynard et al100 suggested that PAT is localized in the mitochondria, where if normal functions of mitochondrial proteins are disrupted by diminished dosage and altered activity, synaptic changes implicated in the pathogenesis of schizophrenia and other psychiatric disorders may occur. Thus, altered dosage of this 22q11 gene could cause developmental or functional consequences, including altered synaptic development or function that could contribute to increased vulnerability for psychopathology in 22q11DS.98,101,102 "
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    ABSTRACT: The 22q11.2 deletion syndrome (22q11DS) is caused by an autosomal dominant microdeletion of chromosome 22 at the long arm (q) 11.2 band. The 22q11DS is among the most clinically variable syndromes, with more than 180 features related with the deletion, and is associated with an increased risk of psychiatric disorders, accounting for up to 1%-2% of schizophrenia cases. In recent years, several genes located on chromosome 22q11 have been linked to schizophrenia, including those encoding catechol-O-methyltransferase and proline dehydrogenase, and the interaction between these and other candidate genes in the deleted region is an important area of research. It has been suggested that haploinsufficiency of some genes within the 22q11.2 region may contribute to the characteristic psychiatric phenotype and cognitive functioning of schizophrenia. Moreover, an extensive literature on neuroimaging shows reductions of the volumes of both gray and white matter, and these findings suggest that this reduction may be predictive of increased risk of prodromal psychotic symptoms in 22q11DS patients. Experimental and standardized cognitive assessments alongside neuroimaging may be important to identify one or more endophenotypes of schizophrenia, as well as a predictive prodrome that can be preventively treated during childhood and adolescence. In this review, we summarize recent data about the 22q11DS, in particular those addressing the neuropsychiatric and cognitive phenotypes associated with the deletion, underlining the recent advances in the studies about the genetic architecture of the syndrome.
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    • "Deletions in this region may contribute to the numerous cognitive and psychiatric disorders associated with 22q11 deletion syndrome (22q11DS). A few examples of these are schizophrenia, autism, attention-deficit disorder and mood disorder (Maynard et al., 2008; Shin et al., 2010). Furthermore, it was found that polymorphisms in the ZDHHC8 gene are associated with smooth pursuit eye movement abnormality in the Korean population (Dunphy et al., 2000). "
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