De novo variants of CSNK2B cause a new intellectual disability-craniodigital syndrome by disrupting the canonical Wnt signaling pathway
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Blood
DISEASE(S): Intellectual Disability
SUBMITTER: 
Prerana Wagle
LAB HEAD: Muhammad Sajid Hussain
PROVIDER: PXD029983 | Pride | 2022-05-04
REPOSITORIES: Pride
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Project description:Main purpose of the project is to delineate the consequences of de novo variants identified in patients manifesting intellectual disability-craniodigital syndrome. By employing pulldown assay coupled with mass spectrometry, we investigated the novel binding partners of CK2β and tried to find the impaired interaction due to variant, CK2β:NP_001311.3;p.Asp32His. Furthermore, we also investigated the effects of mutated CK2β by performing phosphoproteome profiling of patient derived LCLs along with the age and gender matched control.
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Project description:Pesticides are chemical compounds widely used in agriculture to control pests, since the 1960s. Regardless of its specific targets, such substances, unfortunately, can reach the human organism, and negative cumulative effects have been reported in people worldwide. Chronic exposure to pesticides has been discussed as a significant risk factor for the development of cancer, including breast tumors. Breast cancer is the most common malignant neoplasia that affects women worldwide, whose origin is mostly connected to life habits and the environment, and to a lesser extent to inheritable genetic mechanisms. Therefore, the contribution of substances as pesticides, that are present in the environment continuously, may have a pivotal role in the genesis breast cancer, especially in geographic areas in which women are important players in the rural work and are in direct contact with these compounds. In vitro and experimental studies have broadly reported the mechanisms triggered by pesticides that contribute to breast carcinogenesis, which fall essentially within DNA damage-based events in association with hormones deregulation and rising of metabolites that activate oncogenes (Alleva et al., 2018, BRADLOW et al., 1995). However, few is known about how these mechanisms are connected, as well as the manner that they can correlate with disease prognosis and clinicopathological features in human breast cancer as a result of the toxic consequences of pesticide exposure. In the last years, aiming to expand the knowledge about beyond isolated biological findings, high throughput molecular approaches combined with bioinformatics designs raised as powerful tools to understand breast cancer behavior and biology. Thereby, it was possible to broadcast that breast cancer is a very complex disease, and that distinct mechanisms are activated depending on specific clinicopathological characteristics. As far as we know, there are still no studies reporting the use of proteomics-based strategies to assess the impact of chronic pesticide exposure in women with breast cancer. To fill this gap, the present study proposes a toxicoproteomics perspective to investigate the systemic profile of differentially expressed proteins in the blood of breast cancer patients chronically exposed to pesticides, by using a high-throughput label-free proteomic strategy, and provide an integrative clinicopathological view based on bioinformatics approaches and validation experiments.
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Project description:Diabetic cardiomyopathy (DbCM) occurs independently of cardiovascular diseases or hypertension, often leading to heart failure and death. To elucidate the molecular mechanisms involved in the DbCM progress, we performed quantitative proteomic profiling analysis in the left ventricle (LV) of leptin receptor‐deficient mice. Six‐month‐old C57BL/6Jlepr/ lepr (db/db) mice exhibited a phenotype of DbCM. By quantitative shotgun proteomic analysis, we identified 53 differentially expressed proteins in db/db mice, mainly associated with energy metabolism. The subunits of ATP synthase that form the F1 domain and Cytochrome c1, a catalytic core subunit of the complex III that is responsible for electron transfer to Cytochrome c, were upregulated in diabetic LVs. Upregulation of these key proteins may represent an adaptive mechanism by the diabetic heart resulting in increased electron transfer and thereby enhancement of mitochondrial ATP production. Conversely, diabetic LVs also showed a decrease in peptide levels of NADH dehydrogenase 1 beta subcomplex subunit 11, a subunit of complex I that catalyzes the transfer of electrons to ubiquinone. Moreover, an atypical kinase COQ8A, an essential lipid‐soluble electron transporter involved in the biosynthesis of ubiquinone, was also downregulated in diabetic LVs. Our study indicates that despite attempts by hearts from the diabetic mice to augment mitochondrial ATP production, decreased levels of key components of the electron transport chain may contribute to impaired mitochondrial ATP production.
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Project description:Identification of novel, highly penetrant, breast cancer susceptibility genes will require the application of additional strategies beyond that of traditional linkage and candidate gene approaches. Approximately one-third of inherited genetic diseases, including breast cancer susceptibility, are caused by frameshift or nonsense mutations that truncate the protein product [1]. Transcripts harbouring premature termination codons are selectively and rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. Blocking the NMD pathway in any given cell will stabilise these mutant transcripts, which can then be detected using gene expression microarrays. This technique, known as gene identification by nonsense-mediated mRNA decay inhibition (GINI), has proved successful in identifying sporadic nonsense mutations involved in many different cancer types. However, the approach has not yet been applied to identify germline mutations involved in breast cancer. We therefore attempted to use GINI on lymphoblastoid cell lines (LCLs) from multiple-case, non-BRCA1/2 breast cancer families in order to identify additional high-risk breast cancer susceptibility genes. We applied GINI to a total of 24 LCLs,established from breast-cancer affected and unaffected women from three multiple-case non-BRCA1/2 breast cancer families. We then used Illumina gene expression microarrays to identify transcripts stabilised by the NMD inhibition. Total RNA obtained from the lymphoblastoid cell lines derived from 24 individuals.
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Project description:Insufficient leaf photosynthesis promotes sheath NSC transport to the panicle during grain filling. SnRK1 regulates assimilate distribution between plant tissues and organs. However, the mechanism by which SnRK1 regulates sheath NSC transport to the panicle and its response to limited leaf assimilation remain unclear. Here, we performed leaf cutting (LC) at anthesis to simulate insufficient leaf assimilation and set no treatment as a CK. In response to LC, SnRK1 activity increased rapidly, and NSC transport was advanced. Sheath NSCs were not transported in a snrk1a mutant with deficient SnRK1 activity. These results indicated that SnRK1 activity is important for sheath NSC transport. The high correlation of T6P and sucrose and the inhibition of SnRK1 by T6P in sheaths in vitro implied that T6P slightly inhibits SnRK1 activity in rice sheaths in response to sucrose availability. The increase in SnRK1 activity was accompanied by an increase in OsSnRK1a expression and a low sucrose content. Low sucrose signaling increases SnRK1 transcription. Therefore, we speculated that OsSnRK1a expression positively regulates SnRK1 activity in response to low sucrose availability in rice sheaths. Through phosphoproteomics and further PRM verification, 20 phosphosites that depend on SnRK1 and are correlated with NSC transport were obtained. Based on the function of these sites and proteins, we found that SnRK1 regulates starch degradation, sucrose metabolism, phloem transport, sugar transport across tonoplast, and glycolysis via phosphorylation to promote sheath NSC transport. Overall, our results revealed the importance, function and regulatory mechanism of SnRK1 in sheath NSC transport.
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
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