Mutations of DEPDC5 cause autosomal dominant focal epilepsies

Ishida, Saeko; Picard, Fabienne; Rudolf, Gabrielle; Noé, Eric; Achaz, Guillaume; Thomas, Pierre; Genton, Pierre; Mundwiller, Emeline; Wolff, Markus; Marescaux, Christian; Miles, Richard; Baulac, Michel; Hirsch, Édouard; LeGuern, Eric; Baulac, Stéphanie

doi:10.1038/ng.2601

Cited by 214 publications

(204 citation statements)

References 17 publications

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“…3). Of particular note, the first evidence for a genetic link came from inherited focal epilepsies, where loss-of-function mutations in the mammalian SEA1 gene (DEPDC5) have been associated with various forms of this disorder (Baulac, 2014;Dibbens et al, 2013;Ishida et al, 2013;Scheffer et al, 2014). Some of these mutations have been shown to disrupt DEPDC5-dependent inhibition of TORC1 (van Kranenburg et al, 2015).…”

Section: Deregulation Of Gator In Cancer and Other Diseasesmentioning

confidence: 99%

SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

Dokudovskaya

Rout

2015

Journal of Cell Science

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Cells constantly adapt to various environmental changes and stresses. The way in which nutrient and stress levels in a cell feed back to control metabolism and growth are, unsurprisingly, extremely complex, as responding with great sensitivity and speed to the 'feast or famine, slack or stress' status of its environment is a central goal for any organism. The highly conserved target of rapamycin complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses, and plays the key role in the regulation of autophagy. A lot of attention has been paid recently to the factors in this pathway functioning upstream of TORC1. In this Commentary, we focus on a major, newly discovered upstream regulator of TORC1 -the multiprotein SEA complex, also known as GATOR. We describe the structural and functional features of the yeast complex and its mammalian homolog, and their involvement in the regulation of the TORC1 pathway and TORC1-independent processes. We will also provide an overview of the consequences of GATOR deregulation in cancer and other diseases.

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Section: Deregulation Of Gator In Cancer and Other Diseasesmentioning

confidence: 99%

SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

Dokudovskaya

Rout

2015

Journal of Cell Science

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“…These findings suggest that GATOR1 is a tumor suppressor complex upstream of mTORC1. Two independent exome-sequencing analyses of familial focal epilepsy identified loss-of-function mutations in DEPDC5 [114,115], suggesting that hyperactive mTORC1 may cause epilepsy and mTORC1 inhibitors may be used to treat this disorder.…”

Section: Human Diseases Associated With Defects In Amino Acid Sensingmentioning

confidence: 99%

Multiple amino acid sensing inputs to mTORC1

2015

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The evolutionarily conserved target of rapamycin complex 1 (TORC1) is a master regulator of cell growth and metabolism. In mammals, growth factors and cellular energy stimulate mTORC1 activity through inhibition of the TSC complex (TSC1-TSC2-TBC1D7), a negative regulator of mTORC1. Amino acids signal to mTORC1 independently of the TSC complex. Here, we review recently identified regulators that link amino acid sufficiency to mTORC1 activity and how mutations affecting these regulators cause human disease.

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“…Affected individuals do not show cognitive deficits, although some family members exhibit intellectual disability. Recent studies have identified in some of these families mutations in Dishevelled, Egl-10 and Pleckstrin domain-containing protein, the function of which is still unclear, but it might be involved in membrane trafficking, G protein signaling and/or modulation of the mammalian target of rapamycin complex 1 (Table 1) [149][150][151]. Most mutations resulted in a truncated protein and are consistent with loss of function.…”

Section: Familial Focal Epilepsy With Variable Focimentioning

confidence: 86%

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

2014

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Research in genetics of epilepsy represents an area of great interest both for clinical purposes and for understanding the basic mechanisms of epilepsy. Most mutations in epilepsies without structural brain abnormalities have been identified in ion channel genes, but an increasing number of genes involved in a diversity of functional and developmental processes are being recognized through whole exome or genome sequencing. Targeted molecular diagnosis is now available for different forms of epilepsy. The identification of epileptogenic mutations in patients before epilepsy onset and the possibility of developing therapeutic strategies tested in experimental models may facilitate experimental approaches that prevent epilepsy or decrease its severity. Functional analysis is essential for better understanding pathogenic mechanisms and gene interactions. In vitro experimental systems are either cells that usually do not express the protein of interest or neurons in primary cultures. In vivo/ex vivo systems are organisms or preparations obtained from them (e.g., brain slices), which should better model the complexity of brain circuits and actual pathophysiological conditions. Neurons differentiated from induced pluripotent stem cells generated from the skin fibroblasts of patients have recently allowed the study of mutations in human neurons having the genetic background of a given patient. However, there is remarkable complexity underlying epileptogenesis in the clinical dimension, as reflected by the fact that experimental models have not provided yet results having clinical translation and that, with a few exceptions concerning rare conditions, no new curative treatment has emerged from any genetic finding in epilepsy.

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Mutations of DEPDC5 cause autosomal dominant focal epilepsies

Cited by 214 publications

References 17 publications

SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

SEA you later alli-GATOR – a dynamic regulator of the TORC1 stress response pathway

Multiple amino acid sensing inputs to mTORC1

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

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