De novo variants in <scp>CAMK</scp>2A and <scp>CAMK</scp>2B cause neurodevelopmental disorders

Akita, Tenpei; Aoto, Kazushi; Kato, Mitsuhiro; Shiina, Masaaki; Mutoh, Hiroki; Nakashima, Mitsuko; Kuki, Ichiro; Okazaki, Shin; Magara, Shinichi; Shiihara, Takashi; Yokochi, Kenji; Aiba, Kaori; Tohyama, Jun; Ohba, Chihiro; Miyatake, Satoko; Miyake, Noriko; Ogata, Kazuhiro; Fukuda, Atsuo; Matsumoto, Naomichi; Saitsu, Hirotomo

doi:10.1002/acn3.528

Cited by 75 publications

(47 citation statements)

References 35 publications

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“…Shank3 is the one of the most commonly mutated genes in individuals diagnosed with autism spectrum disorders (ASD) and is also linked to other neuropsychiatric disorders (Gauthier et al, 2010, Herbert, 2011. Functionally disruptive missense mutations in CaMKIIa and LTCCs have also been identified in patients with ASD and other neurodevelopmental disorders (Akita et al, 2018, Chia et al, 2018, Kury et al, 2017, Limpitikul et al, 2016, Moon et al, 2018, Nyegaard et al, 2010, Pinggera et al, 2015, Pinggera et al, 2017, Pinggera & Striessnig, 2016, Proietti Onori et al, 2018, Stephenson et al, 2017. In addition, the expression of c-fos, a well-studied target of CREB-mediated gene expression, is dysregulated in rodent models of autism (Dubiel & Kulesza, 2015, Orlandini et al, 1996, Williams & Umemori, 2014.…”

Section: Camkii Signaling In Shank3-related Neurological Disordersmentioning

confidence: 99%

“…For example, Ca 2+ -dependent phosphorylation of the nuclear transcription factor CREB at Ser 133 leads to the transcription of immediate-early genes encoding multiple proteins (e.g., c-fos, BDNF, homer1a) that play key roles in learning and memory (Bading, 2013, Benito et al, 2011, Dolmetsch, 2003, Flavell & Greenberg, 2008. Multiple neuropsychiatric disorders are associated with disruptions in activity-dependent gene expression (Ebert & Greenberg, 2013, Gallo et al, 2018, and these disorders have been linked to mutations in Ca 2+ signaling proteins, such as L-type calcium channels (LTCCs) and calcium/calmodulin-dependent protein kinase II (CaMKII) (Akita et al, 2018, Chia et al, 2018, Kury et al, 2017, Limpitikul et al, 2016, Moon et al, 2018, Nyegaard et al, 2010, Pinggera et al, 2015, Pinggera et al, 2017, Pinggera & Striessnig, 2016, Proietti Onori et al, 2018, Stephenson et al, 2017. For example, Timothy Syndrome is caused by mutations in the CaV1.2 LTCC a1 subunit that disrupt neuronal excitation-transcription (E-T) coupling (Li et al, 2016), contributing to the neurobehavioral symptoms of this complex multi-system disorder, including autism spectrum disorder (ASD).…”

Section: Introductionmentioning

confidence: 99%

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Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction

Perfitt

Wang

Stephenson

et al. 2019

Preprint

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The molecular mechanisms that couple plasma membrane receptors/channels to specific intracellular responses, such as increased gene expression, are incompletely understood. The postsynaptic scaffolding protein Shank3 associates with Ca 2+ permeable receptors or ion channels that can activate many downstream signaling proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII). Here, we show that Shank3/CaMKIIa complexes can be specifically co-immunoprecipitated from mouse forebrain lysates, and that purified activated (Thr286 autophosphorylated) CaMKIIa binds directly to Shank3 between residues 829-1130. Mutation of three basic residues in Shank3 (R 949 RK 951 ) to alanine disrupts CaMKII binding to Shank3 fragments in vitro, as well as CaMKII association with full-length Shank3 in heterologous cells. Our shRNA/rescue studies revealed that Shank3 binding to both CaMKII and L-type calcium channels (LTCCs) is required for increased phosphorylation of the nuclear CREB transcription factor induced by depolarization of cultured hippocampal neurons. Thus, this novel Shank3-CaMKII interaction is essential for the initiation of a specific long-range signal from plasma membrane LTCCs to the nucleus that is required for activitydependent changes in neuronal gene expression during learning and memory.

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Section: Camkii Signaling In Shank3-related Neurological Disordersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction

Perfitt

Wang

Stephenson

et al. 2019

Preprint

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“…The generation of different Camk2a mutants (of which the knock-out was already published Ͼ25 years ago (Silva et al, 1992a,b)) and Camk2b mutants, greatly contributed to the understanding of the role of these two isoforms in neuronal functioning, learning, and plasticity in mice (Mayford et al, 1995;Giese et al, 1998;Elgersma et al, 2002;Borgesius et al, 2011;Achterberg et al, 2014;Kool et al, 2016). Very recently, the importance of CAMK2A and CAMK2B for normal human neuro-development was shown (Küry et al, 2017;Stephenson et al, 2017;Akita et al, 2018;Chia et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

CAMK2-Dependent Signaling in Neurons Is Essential for Survival

Kool¹,

Onori

Borgesius³

et al. 2019

J. Neurosci.

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Ca 2ϩ /calmodulin-dependent protein kinase II (CAMK2) is a key player in synaptic plasticity and memory formation. Mutations inCamk2a or Camk2b cause intellectual disability in humans, and severe plasticity and learning deficits in mice, indicating unique functions for each isoform. However, considering the high homology between CAMK2A and CAMK2B, it is conceivable that for critical functions, one isoform compensates for the absence of the other, and that the full functional spectrum of neuronal CAMK2 remains to be revealed.Here we show that germline as well as adult deletion of both CAMK2 isoforms in male or female mice is lethal. Moreover, Ca 2ϩdependent activity as well as autonomous activity of CAMK2 is essential for survival. Loss of both CAMK2 isoforms abolished LTP, whereas synaptic transmission remained intact. The double-mutants showed no gross morphological changes of the brain, and in contrast to the long-considered role for CAMK2 in the structural organization of the postsynaptic density (PSD), deletion of both CAMK2 isoforms did not affect the biochemical composition of the PSD. Together, these results reveal an essential role for CAMK2 signaling in early postnatal development as well as the mature brain, and indicate that the full spectrum of CAMK2 requirements cannot be revealed in the single mutants because of partial overlapping functions of CAMK2A and CAMK2B. CAMK2A and CAMK2B have been studied for over 30 years for their role in neuronal functioning. However, most studies were performed using single knock-out mice. Because the two isoforms show high homology with respect to structure and function, it is likely that some redundancy exists between the two isoforms, meaning that for critical functions CAMK2B compensates for the absence of CAMK2A and vice versa, leaving these functions to uncover. In this study, we generated Camk2a/Camk2b doublemutant mice, and observed that loss of CAMK2, as well as the loss of Ca 2ϩ -dependent and Ca 2ϩ -independent activity of CAMK2 is lethal. These results indicate that despite 30 years of research the full spectrum of CAMK2 functioning in neurons remains to be unraveled.

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“…The behavioural, histological and cellular phenotypes of the human mutations have been documented (18, 19), but these phenotypes are too downstream to decipher their molecular basis. This study shows that the mutated residue positions are distributed along the allosteric signal relays generated by R1 capture and strengthened by T286 phosphorylation to provide, for the first time, a molecular rationale.…”

Section: Discussionmentioning

confidence: 99%

Conformational coupling by trans-phosphorylation in calcium calmodulin dependent kinase II

Pandini

Schulman

Khan

2019

Preprint

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31The calcium calmodulin dependent protein kinase II (CaMKII) is a dodecameric holoenzyme 32 important for encoding memory. Its activation, triggered by binding of calcium calmodulin, persists 33 autonomously after calmodulin dissociation. One (receiver) kinase captures and subsequently phos-34 phorylates the regulatory domain peptide of a donor kinase forming a chained dimer as a first stage 35 of autonomous activation. Protein dynamics simulations examined the conformational changes trig-36 gered by dimer formation and phosphorylation, aimed to provide a molecular rationale for human 37 mutations that result in learning disabilities. Ensembles generated from X-ray crystal structures were 38 characterized by network centrality and community analysis. Mutual information related collective 39 motions to local fragment dynamics encoded with a structural alphabet. Implicit solvent tCONCOORD 40 conformational ensembles revealed the dynamic architecture of Inactive kinase domains was co-opted 41 in the activated dimer but the network hub shifted from the nucleotide binding cleft to the captured 42 peptide. Explicit solvent molecular dynamics (MD) showed nucleotide and substrate binding determi-43 nants formed coupled nodes in long-range signal relays between regulatory peptides in the dimer. 44Strain in the extended captured peptide was balanced by reduced flexibility of the receiver kinase C-45 lobe core. The relays were organized around a hydrophobic patch between the captured peptide and 46a key binding helix. The human mutations aligned along the relays. Thus, these mutations could disrupt 47 Author Summary 58Protein kinases play central roles in intracellular signalling. Auto-phosphorylation by bound 59 nucleotide typically precedes phosphate transfer to multiple substrates. Protein conformational 60 changes are central to kinase function, altering binding affinities to change cellular location and shunt 61 from one signal pathway to another. In the brain, the multi-subunit kinase, CaMKII is activated by cal-62 cium calmodulin upon calcium jumps produced by synaptic stimulation. Auto-transphosphorylation of 63 a regulatory peptide enables the kinase to remain activated and mediate long-term behavioural effects 64 after return to basal calcium levels. A database of mutated residues responsible for these effects is 65 difficult to reconcile solely with impaired nucleotide or substrate binding. Therefore, we have compu-66 tationally generated interaction networks to map the conformational plasticity of the kinase domains 67where most mutations localize. The network generated from the atomic structure of a phosphorylated 68 dimer resolves protein sectors based on their collective motions. The sectors link nucleotide and sub-69 strate binding sites in self-reinforcing relays between regulatory peptides. The self-reinforcement is 70 strengthened by phosphorylation consistent with the reported positive cooperativity of kinase activity 71 with calcium-calmodulin concentration. The network gives a better match with the mu...

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De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

Cited by 75 publications

References 35 publications

Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction

Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction

CAMK2-Dependent Signaling in Neurons Is Essential for Survival

Conformational coupling by trans-phosphorylation in calcium calmodulin dependent kinase II

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