Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy

Shimojima, Keiko; Sugawara, Midori; Shichiji, M.; Mukaida, Souichi; Takayama, Rumiko; Imai, Katsumi; Yamamoto, Toshiyuki

doi:10.1038/jhg.2011.58

Cited by 76 publications

(90 citation statements)

References 19 publications

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“…10,11,32,33 This hyperactivation of the mTORC1 pathway has been shown to stimulate excessive protein synthesis in neuronal cells, leading to disturbances in neuronal differentiation and morphology, synaptic connectivity, and plasticity. Loss-of-function variants in CB, which are known to reduce GABAergic transmission and alter synaptic plasticity, have been associated with overlapping phenotypes, that is, intellectual disability, epilepsy, anxiety, 15,[22][23][24][25] and now autism, present in the patient here described. Therefore, the data presented here point to the possibility that mTORC1 pathway overactivation in CB-deficient neuronal cells might also contribute to the cognitive and behavioral abnormalities in patients with loss-of-function variants in CB.…”

Section: Discussionmentioning

confidence: 80%

“…Primary fibroblasts from K401 and from two sex-and agematched controls were reprogrammed using standard retroviral reprogramming technology. 24 We obtained at least two clones from each K401-iPSC and control iPSC, which were subsequently differentiated into iNPCs and iNeurons (for the primary purpose of confirming the differentiation potential of iNPCs into mature neurons). Expression of pluripotency-, NPC-, and neuron-specific markers was determined by immunocytochemistry ( Figure 2A).…”

Section: Generation Of Ipscs and Neural Progenitor Cells From K401 Pamentioning

confidence: 99%

“…Consequently, dysregulation of mTORC1 activity might contribute to some of the neurological abnormalities observed in patients with CB variants, such as intellectual disability, epilepsy, and anxiety. 15,[22][23][24][25] However, to our knowledge, there are no published studies addressing these questions.…”

Section: Introductionmentioning

confidence: 99%

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Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

et al. 2015

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Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuronspecific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.

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Section: Discussionmentioning

confidence: 80%

Section: Generation Of Ipscs and Neural Progenitor Cells From K401 Pamentioning

confidence: 99%

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Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

et al. 2015

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“…The significance of CB for glycinergic and GABAergic synaptic function is underscored by the discovery of several loss of function mutations in ARGEF9 underlying severe forms of X-linked mental retardation and hyperekpleksia [42,43]. In recombinant expression systems, CB is essential for cell-surface translocation of gephyrin [44].…”

Section: Collybistinmentioning

confidence: 99%

Molecular and functional heterogeneity of GABAergic synapses

Fritschy

Panzanelli

Tyagarajan

2012

Cell. Mol. Life Sci.

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Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA(A) receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA(A) receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA(A) receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapses. AbstractKnowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA A receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA A receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA A receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophinglycoprotein complex to the molecular ...

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“…Together, these findings suggest that CB might also interact with mTOR and modulate mTORC1 signaling and protein synthesis. Consequently, abnormal mTORC1 activity might contribute to some of the atypical neurological phenotypes observed in patients with CB mutations, such as mental retardation, epilepsy and autism (12,(18)(19)(20)(21). However, to our knowledge, there are no published studies addressing these questions.…”

Section: Introductionmentioning

confidence: 55%

Estudo do envolvimento da proteína colibistina no controle do início da tradução

Machado¹

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Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy

Cited by 76 publications

References 19 publications

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

Molecular and functional heterogeneity of GABAergic synapses

Estudo do envolvimento da proteína colibistina no controle do início da tradução

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