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Schematic of microdeletions observed in the cohort. The borders of the minimal overlapping region (MOR) are demarcated by dotted lines encompassing seven genes.
Source publication
The original version of this Article contained an error in the spelling of the author Siddharth Banka, which was incorrectly given as Siddhart Banka. This has now been corrected in both the PDF and HTML versions of the Article.
Context in source publication
Context 1
... Four individuals had mild dysmorphic features ( Table 1, Fig. 1). The three Caucasian individuals for whom images are available ( Fig. 1) share facial similarities such as a sloping forehead, a long tubular nose with a prominent columella, and a prominent chin. CMA identified overlapping microdeletions on the short arm of chromosome 16 (16p13.3; Fig. 2). There is no overlap with the 16p13.3 ...
Citations
... C, D Expression levels of p-PDK1, PDK1, PI3K, p-PI3K, p-Akt, Akt and Bcl-2 in hepatocytes (n = 6). * p < 0.05, ** p < 0.001: versus indicated group PDK1 is a phosphorylation-regulated kinase expressed in various eukaryotic organs that plays a central role in activating diverse cell signaling pathways [24,25]. PI3K activation generates phosphatidylinositol-3,4,5-triphosphate [26], and subsequently recruits PDK1 and Akt to the plasma membrane. ...
Background
Gynostemma pentaphyllum (Thunb.) Makino, commonly known as “southern ginseng”, contains high amounts of ginsenoside derivatives and exhibits similar biological activities with Panax ginseng (C. A. MEY) (ginseng), which is usually used as a low-cost alternative to ginseng. G. pentaphyllum has therapeutic effects on liver diseases. However, the mechanisms underlying its hepatoprotective action have not been fully elucidated.
Methods
The protective effects of the ethanolic extract of G. pentaphyllum (GPE) were evaluated using an experimental carbon tetrachloride (CCl 4 )-induced liver disease model. Potential targets of GPE were predicted using the “Drug-Disease” bioinformatic analysis. Furthermore, comprehensive network pharmacology and transcriptomic approaches were employed to investigate the underlying mechanisms of GPE in the treatment of liver disease.
Results
The pathological examinations showed that GPE significantly alleviated hepatocyte necrosis and liver injury. GPE significantly downregulated Bax and cleaved-PARP expression and upregulated Bcl-2 expression during CCl 4 -induced hepatocyte apoptosis. We compared the effects of four typical compounds in GPE -a ginsenoside (Rb3) shared by both GPE and ginseng and three unique gypenosides in GPE. Notably, Gypenoside A (GPA), a unique saponin in GPE, markedly reduced hepatocyte apoptosis. In contrast, ginsenoside Rb3 had a weaker effect. Network pharmacology and transcriptomic analyses suggested that this anti-apoptotic effect was achieved by upregulating the PI3K/Akt signaling pathway mediated by PDK1.
Conclusions
These results suggested that G. pentaphyllum had a promising hepatoprotective effect, with its mechanism primarily involving the upregulation of the PDK1/Bcl-2 signaling pathway by GPA, thereby preventing cell apoptosis.
Graphic Abstract
... microdeletion syndrome featured by simultaneous haploinsufficiency of TBC1D24, ATP6V0C, and PDPK1 could induce epileptic disorders, microcephaly, and developmental delay. 52 A previous study also reported that the balloon cell in FCD type II has stronger p-PDK1 (Ser241) staining than dysmorphic neurons. 53 The Pattern A was enriched in ROS signaling, which could be explained by oxidative stress related to FCD and seizure onset. ...
... PDPK1, 3-phosphoinositide-dependent protein kinase 1, also known as PDK1, is a phosphorylationregulated kinase that is expressed in various organs of eukaryotes and plays a central role in activating a variety of cell signaling pathways 14,15,16 . Studies have found that when cells are infected by external viruses, PDPK1 is released from the endoplasmic reticulum and translocated to the cell membrane, resulting in the phosphorylation of AKT and activation of the AKT-mTOR pathway, ultimately inhibiting autophagy 17 . ...
Health risk stemming from drinking alcohol is serious, sometimes even life-threatening. Alcoholic steatohepatitis (ASH) is a critical stage leading to cirrhosis and end-stage liver disease. However, its pathogenesis is still far from clearly understood and an effective treatment recognized widely haven’t been discovered. Interestingly, PDPK1, 3-phosphoinositide-dependent protein kinase 1, also known as PDK1, were observed obviously increased in ASH model by our researchers. Meanwhile, we also investigated the protective role of autophagy playing in ASH. Here, we studied the function of PDPK1 and found an efficient treatment to alleviate symptoms by targeting PDPK1 in ASH. In our study, PDPK1 affects hepatocyte self-healing by inhibiting autophagy. Both inhibiting PDPK1 and the phosphorylation of PDPK1(ser241) could protect hepatocyte from suffering heavy alcoholic hepatitis.
... In summary, we demonstrate that 2q34 deletions that result in loss of exons of ERBB4 may cause autosomal dominant mild to moderate developmental delay, ID or epilepsy. CNVs can help to identify novel disease-genes [22][23][24]. This study, therefore, adds ERBB4 as a likely new candidate gene for ID. ...
ERBB4 encodes the tyrosine kinase receptor HER4, a critical regulator of normal cell function and neurodevelopmental processes in the brain. One of the key ligands of HER4 is neureglin-1 (NRG1), and the HER4-NRG1 signalling pathway is essential in neural crest cell migration, and neuronal differentiation. Pharmacological inactivation of HER4 has been shown to hasten the progression of epileptogenesis in rodent models, and heterozygous ERBB4 null mice are shown to have cognitive deficits and delayed motor development. Thus far there is only a single case report in the literature of a heterozygous ERBB4 deletion in a patient with intellectual disability (ID). We identified nine subjects from five unrelated families with chromosome 2q34 deletions, resulting in heterozygous intragenic loss of multiple exons of ERBB4, associated with either non-syndromic ID or generalised epilepsy. In one family, the deletion segregated with ID in five affected relatives. Overall, this case series further supports that haploinsufficiency of ERBB4 leads to non-syndromic intellectual disability or epilepsy.
... The WBS neuropsychological profile is characterized by social disinhibition and excessive empathy which do [12] Gene function [13] Animal study [14] Reported in association with autism [15,16] Reported in association with neuropsychiatric disorders [17] Autism candidate gene [18,19] WES whole exome sequencing, WBS Williams Beuren Syndrome, NA not available, ND not done, P pathogenic, C contradictory, B benign, I intermediary not follow common social norms; therefore, the terms "overfriendliness" and "hypersociability" appear to be a misleading oversimplification. Excessive talkativeness is often not directed toward others, and verbal communication can be therefore impaired in WBS as in ASD. ...
Abstract Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as “overfriendliness” and “hyersociability”. WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic. Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin. The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in “typical” WBS patients: therefore, the terms “overfriendliness” and “hypersociability” appear to be a misleading oversimplification. The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit.
The health risk stemming from drinking alcohol is serious, sometimes even life-threatening. Alcoholic steatohepatitis (ASH) is a critical stage leading to cirrhosis and end-stage liver disease. However, its pathogenesis is still far from clearly understood, and a treatment that is widely recognised as effective has not been discovered. Interestingly, PDPK1,3-phosphoinositide-dependent protein kinase 1, also known as PDK1, was observed to be obviously increased in the ASH model by our researchers. We also investigated the protective role of autophagy in ASH. Here, we studied the function of PDPK1 and found an efficient treatment to alleviate symptoms by targeting PDPK1 in ASH. In our study, PDPK1 affected hepatocyte self-healing by inhibiting autophagy. Both inhibiting PDPK1 and the phosphorylation of PDPK1 (ser241) could protect hepatocytes from suffering heavy alcoholic hepatitis.
