Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Genotyping data from one patient with unexplained mental retardation and a deletion in 15q13

ABSTRACT: Recurrent deletions on 15q13.3 have been identified as a predisposition to mental retardation, epilepsy and psychiatric disease. We report compound heterozygous deletions on 15q13.3 in one patients with severe encephalopathy and seizures. We analysed two independent patients with severe encephalopathy and seizures and found heterozygous deletions on 15q13.3 in both patients.

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Bonin

PROVIDER: E-GEOD-20564 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Developmental and epileptic encephalopathy is a group of rare, severe neurodevelopmental disorders characterized by the co-occurrence of epilepsy and intellectual disability (ID), in which there is additional developmental impairment independent of epileptic activity. In 2009, through a chemical mutagenesis screen performed in mice, it was found that mutations in Seizure threshold 2 (SZT2) trigger a higher susceptibility to seizures in a semidominant manner. Since then 27 patients have been identified with biallelic SZT2 mutations (in compound heterozygous or homozygous state), all of them displaying developmental delay of varying severity and dysmorphic features such as macrocephaly. Patients commonly suffer from recurrent epileptic seizures that often are refractory to available therapies. Human SZT2 encodes a 3,375 amino acids protein highly conserved throughout evolution, that is predominantly expressed in embryonal stages and in the adult the brain. The molecular functions of SZT2 protein are largely unknown however it has been reported that SZT2 forms a complex with KPTN, ITFG2, and C12orf66. This complex, named KICSTOR, senses aminoacid depletion and functions as a negative regulator of mTORC1 under catabolic conditions. Taking into consideration that SZT2 remain one of the least characterized regulators of mTORC1 we decided to decipher its interactome under catabolic and anabolic conditions. We found mTORC1 and AMPK signaling components enriched in the SZT2 interactome, but also prominent clusters of autophagy and ciliogenesis regulators as well as a significant number of hits that regulate neurogenesis and neurodegenerative processes. We have validated a few key hits from the interactome, including proteins involved in cilliogenesis and epilepsy. The detailed analysis of the SZT2KOs demonstrated that although these cells show increased mTORC1 signaling that can be prevented by treatment with either rapamycin or torin, they also contra intuitively display increased autophagy that is independent of the physiological conditions tested. These results are in accordance with our interactome data were we detect a significant pool of selective autophagy receptors/regulators. Overall the presented data should serve as a tool to address the physiological functions of SZT2 in more comprehensive manner. In the manuscript discussion we put forward our model in which SZT2 plays a broader role in the coordination of cellular metabolism than previously anticipated.

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Genotyping data from one patient with unexplained mental retardation and a deletion in 15q13

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