Defective lipid signalling caused by mutations in<i>PIK3C2B</i>underlies focal epilepsy

Gozzelino, Luca; Kochlamazashvili, Gaga; Baldassari, Sara; Mackintosh, Albert Ian; Iovino, Emanuela; Liu, Yu‐Chi; Bennett, Caitlin A.; Bennett, Mark F; Damiano, John A.; Marconi, Caterina; Giangregorio, Tania; Magini, Pamela; Kuijpers, Marijn; Maritzen, Tanja; Norata, Giuseppe Danilo; Baulac, Stéphanie; Canafoglia, Laura; Seri, Marco; Tinuper, Paolo; Scheffer, Ingrid E.; Bahlo, Melanie; Berkovic, Samuel F.; Hildebrand, Michael S.; Kunz, Wolfram S.; Giordano, Lucio; Bisulli, Francesca; Martini, Miriam; Haucke, Volker; Hirsch, Emilio; Pippucci, Tommaso

doi:10.1093/brain/awac082

Cited by 15 publications

(7 citation statements)

References 66 publications

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“…S4 C and D ) suggest that PI3KC2β may act on a different pool of 3-phosphoinositides, e.g., via synthesis of PI(3,4)P 2 ( 16 , 19 ). To test this we capitalized on a class III-like mutant version of PI3KC2β, which is selectively defective in PI(3,4)P 2 synthesis but can generate PI(3)P with WT efficacy ( 16 , 41 ). Strikingly, reexpression of mutant class III-like PI3KC2β failed to restore normal levels of β1-integrins in HeLa cells depleted of the endogenous enzyme ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model

Samsó

Koch

Posor

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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X-linked centronuclear myopathy (XLCNM) is a severe human disease without existing therapies caused by mutations in the phosphoinositide 3-phosphatase MTM1. Loss of MTM1 function is associated with muscle fiber defects characterized by impaired localization of β-integrins and other components of focal adhesions. Here we show that defective focal adhesions and reduced active β-integrin surface levels in a cellular model of XLCNM are rescued by loss of phosphatidylinositiol 3-kinase C2β (PI3KC2β) function. Inactivation of the Mtm1 gene impaired myoblast differentiation into myotubes and resulted in reduced surface levels of active β1-integrins as well as corresponding defects in focal adhesions. These phenotypes were rescued by concomitant genetic loss of Pik3c2b or pharmacological inhibition of PI3KC2β activity. We further demonstrate that a hitherto unknown role of PI3KC2β in the endocytic trafficking of active β1-integrins rather than rescue of phosphatidylinositol 3-phosphate levels underlies the ability of Pik3c2b to act as a genetic modifier of cellular XLCNM phenotypes. Our findings reveal a crucial antagonistic function of MTM1 and PI3KC2β in the control of active β-integrin surface levels, thereby providing a molecular mechanism for the adhesion and myofiber defects observed in XLCNM. They further suggest specific pharmacological inhibition of PI3KC2β catalysis as a viable treatment option for XLCNM patients.

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Section: Resultsmentioning

confidence: 99%

Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model

Samsó

Koch

Posor

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Germline or somatic mutations in components of PI3K family are frequent in congenital vascular disorders, with mTOR signaling playing a central role in such pathogenesis ( 4 ). Ultra-rare variants in PIK3C2B cause focal epilepsy in humans ( 43 ), and on the basis of our data, it is tempting to speculate that these patients also have a predisposition to develop vascular anomalies, perhaps in an epistatic context. This may be relevant to some patients with vascular malformations associated with high PI3K/mTORC1 signaling for which the genetic cause is unknown ( 4 , 44 , 45 ).…”

Section: Discussionmentioning

confidence: 75%

PI3K-C2β limits mTORC1 signaling and angiogenic growth

Kobialka,

Llena,

Deleyto-Seldas

et al. 2023

Sci. Signal.

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Phosphoinositide 3-kinases (PI3Ks) phosphorylate intracellular inositol lipids to regulate signaling and intracellular vesicular trafficking. Mammals have eight PI3K isoforms, of which class I PI3Kα and class II PI3K-C2α are essential for vascular development. The class II PI3K-C2β is also abundant in endothelial cells. Using in vivo and in vitro approaches, we found that PI3K-C2β was a critical regulator of blood vessel growth by restricting endothelial mTORC1 signaling. Mice expressing a kinase-inactive form of PI3K-C2β displayed enlarged blood vessels without corresponding changes in endothelial cell proliferation or migration. Instead, inactivation of PI3K-C2β resulted in an increase in the size of endothelial cells, particularly in the sprouting zone of angiogenesis. Mechanistically, we showed that the aberrantly large size of PI3K-C2β mutant endothelial cells was caused by mTORC1 activation, which sustained growth in these cells. Consistently, pharmacological inhibition of mTORC1 with rapamycin normalized vascular morphogenesis in PI3K-C2β mutant mice. Together, these results identify PI3K-C2β as a crucial determinant of endothelial signaling and illustrate the importance of mTORC1 regulation during angiogenic growth.

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“…Nesrin et al [ 37 ] showed that PIK3C2B (Phosphatidylinositol-4-Phosphate 3-Kinase Catalytic Subunit Type 2 Beta) could trigger specific muscle ablation and is identified as a genetic modifier of MTM1 mutation, and here we know that mutation of MTM1 is the cause of myotubular myopathy. On the other hand, some studies have confirmed that heterozygous ultrarare variants in PIK3C2B could cause defective lipid signals [ 38 ]. According to these findings, the changes in muscle and fat in vivo may be related to the differential expression of PIK3C2B .…”

Section: Discussionmentioning

confidence: 99%

Integration of Selection Signatures and Protein Interactions Reveals NR6A1, PAPPA2, and PIK3C2B as the Promising Candidate Genes Underlying the Characteristics of Licha Black Pig

Xie

Zhang

Chen

et al. 2023

Biology

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Licha black (LI) pig has the specific characteristics of larger body length and appropriate fat deposition among Chinese indigenous pigs. Body length is one of the external traits that affect production performance, and fat deposition influences meat quality. However, the genetic characteristics of LI pigs have not yet been systematically uncovered. Here, the genomic information from 891 individuals of LI pigs, commercial pigs, and other Chinese indigenous pigs was used to analyze the breed characteristics of the LI pig with runs of homozygosity, haplotype, and FST selection signatures. The results showed the growth traits-related genes (i.e., NR6A1 and PAPPA2) and the fatness traits-related gene (i.e., PIK3C2B) were the promising candidate genes that closely related to the characteristics of LI pigs. In addition, the protein–protein interaction network revealed the potential interactions between the promising candidate genes and the FASN gene. The RNA expression data from FarmGTEx indicated that the RNA expression levels of NR6A1, PAPPA2, PIK3C2B, and FASN were highly correlated in the ileum. This study provides valuable molecular insights into the mechanisms that affect pig body length and fat deposition, which can be used in the further breeding process to improve meat quality and commercial profitability.

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Defective lipid signalling caused by mutations inPIK3C2Bunderlies focal epilepsy

Cited by 15 publications

References 66 publications

Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model

Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model

PI3K-C2β limits mTORC1 signaling and angiogenic growth

Integration of Selection Signatures and Protein Interactions Reveals NR6A1, PAPPA2, and PIK3C2B as the Promising Candidate Genes Underlying the Characteristics of Licha Black Pig

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