Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly

Capo‐Chichi, José‐Mario; Tcherkezian, Joseph; Hamdan, Fadi F.; Décarie, Jean Claude; Dobrzeniecka, Sylvia; Patry, Lysanne; Nadon, M. A.; Mucha, Bettina; Major, Philippe; Shevell, Michael; Bencheikh, Bouchra Ouled Amar; Joober, Ridha; Samuels, Mark E.; Rouleau, Guy A.; Roux, Philippe P.; Michaud, Jacques L.

doi:10.1136/jmedgenet-2013-101680

Cited by 46 publications

(32 citation statements)

References 14 publications

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“…Two recent studies have described humans carrying mutations in TBC1D7 , which manifested clinically with intellectual disability, macrocrania (large skull), and anxiety. Since none of the cases had epilepsy, autism, tubers, or SENs, TBC1D7 mutations seem to diverge phenotypically from TSC1/2 mutations, at least in brain(Alfaiz et al, 2014; Capo-Chichi et al, 2013). …”

Section: Neuropathology Of Mtormentioning

confidence: 97%

The Neurology of mTOR

Lipton

Şahin

2014

Neuron

627

534

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The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.

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Section: Neuropathology Of Mtormentioning

confidence: 97%

The Neurology of mTOR

Lipton

Şahin

2014

Neuron

627

534

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“…Mutations in TBC1D7 (REF. 61), a binding partner of the TSC1-TSC2 complex, have been associated with intellectual disability and megalencephaly 62,63 . These cases were not associated with epilepsy, autism, or FCD; thus, TBC1D7 mutations result in disorders that are phenotypically distinct from TSC1 and TSC2 mutations.…”

Section: Pten Mutationsmentioning

confidence: 99%

The mTOR signalling cascade: paving new roads to cure neurological disease

2016

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Defining the multiple roles of the mechanistic (formerly 'mammalian') target of rapamycin (mTOR) signalling pathway in neurological diseases has been an exciting and rapidly evolving story of bench-to-bedside translational research that has spanned gene mutation discovery, functional experimental validation of mutations, pharmacological pathway manipulation, and clinical trials. Alterations in the dual contributions of mTOR - regulation of cell growth and proliferation, as well as autophagy and cell death - have been found in developmental brain malformations, epilepsy, autism and intellectual disability, hypoxic-ischaemic and traumatic brain injuries, brain tumours, and neurodegenerative disorders. mTOR integrates a variety of cues, such as growth factor levels, oxygen levels, and nutrient and energy availability, to regulate protein synthesis and cell growth. In line with the positioning of mTOR as a pivotal cell signalling node, altered mTOR activation has been associated with a group of phenotypically diverse neurological disorders. To understand how altered mTOR signalling leads to such divergent phenotypes, we need insight into the differential effects of enhanced or diminished mTOR activation, the developmental context of these changes, and the cell type affected by altered signalling. A particularly exciting feature of the tale of mTOR discovery is that pharmacological mTOR inhibitors have shown clinical benefits in some neurological disorders, such as tuberous sclerosis complex, and are being considered for clinical trials in epilepsy, autism, dementia, traumatic brain injury, and stroke.

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“…Intriguingly, overexpression of TBC1D7 was also reported to increase mTORC1 activity (23). TBC1D7 mutations have not been found in TSC patients, but homozygous loss of TBC1D7 causes intellectual disability and megalencephaly, a developmental disorder associated with mTORC1 activation (27). Genome-wide brain tissue expression analysis also identified TBC1D7 as a susceptibility locus for migraine (28).…”

mentioning

confidence: 98%

Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7)

Qin

Wang

Hoogeveen‐Westerveld

et al. 2016

Journal of Biological Chemistry

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Mutations in TSC1 or TSC2 cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by the occurrence of benign tumors in various vital organs and tissues. TSC1 and TSC2, the TSC1 and TSC2 gene products, form the TSC protein complex that senses specific cellular growth conditions to control mTORC1 signaling. TBC1D7 is the third subunit of the TSC complex, and helps to stabilize the TSC1-TSC2 complex through its direct interaction with TSC1. Homozygous inactivation of TBC1D7 causes intellectual disability and megaencephaly. Here we report the crystal structure of a TSC1-TBC1D7 complex and biochemical characterization of the TSC1-TBC1D7 interaction. TBC1D7 interacts with the C-terminal region of the predicted coiled-coil domain of TSC1. The TSC1-TBC1D7 interface is largely hydrophobic, involving the ␣4 helix of TBC1D7. Each TBC1D7 molecule interacts simultaneously with two parallel TSC1 helices from two TSC1 molecules, suggesting that TBC1D7 may stabilize the TSC complex by tethering the C-terminal ends of two TSC1 coiled-coils.Tuberous sclerosis complex (TSC) 4 is a multisystem genetic disease that is characterized by the development of hamartomas or benign tumors in various organs, including skin, brain, and kidneys, and is frequently associated with epilepsy, intellectual disability, and autism (1, 2). TSC is caused by mutations to either of two genes, TSC1 and TSC2, which encode for proteins hamartin (TSC1) and tuberin (TSC2), respectively. TSC1 and TSC2 form a protein complex that acts as a GTPase-activating protein (GAP) for the small G-protein Rheb, which in turn serves as a crucial activator of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). The TSC complex is a tumor suppressor, inhibiting the Rheb-mTORC1-dependent stimulation of anabolic metabolism and cell growth (2-11). TSC2 contains a GAP domain and is the catalytic subunit of the complex. TSC1 is believed to enhance TSC2 function by activating TSC2 GAP activity, stabilizing TSC2, and/or maintaining the correct intracellular localization of the TSC complex (12-19). Recent work indicates that TSC1 might also have TSC2-independent activities in the cell (20 -22).Tre2-Bub2-Cdc16 domain family member 7 (TBC1D7) is a TSC1-binding protein (23-25), and has been recently identified as the third subunit of the TSC complex (25). TSC1, TSC2, and TBC1D7 form the core of the TSC protein complex in the cell, which migrates in size exclusion chromatography with a peak mass of ϳ2 MDa (26). Consistent with its important role in the TSC protein complex, knockdown of TBC1D7 results in decreased association of TSC1 and TSC2, leading to decreased Rheb-GAP activity, increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions (25). Intriguingly, overexpression of TBC1D7 was also reported to increase mTORC1 activity (23). TBC1D7 mutations have not been found in TSC patients, but homozygous loss of TBC1D7 causes intellectual disability and megalencephaly, a developmental disorder a...

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Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly

Cited by 46 publications

References 14 publications

The Neurology of mTOR

The Neurology of mTOR

The mTOR signalling cascade: paving new roads to cure neurological disease

Structural Basis of the Interaction between Tuberous Sclerosis Complex 1 (TSC1) and Tre2-Bub2-Cdc16 Domain Family Member 7 (TBC1D7)

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