Insights Into the Mechanisms of Epilepsy from Structural Biology of LGI1–ADAM22

Cellular and Molecular Life Sciences (2020) 77:267–274 https://doi.org/10.1007/s00018-019-03269-0 Cellular andMolecular Life Sciences

REVIEW

Insights into the mechanisms of epilepsy from structural biology of LGI1–ADAM22

Atsushi Yamagata1,2,3,4 · Shuya Fukai1,2,3

Received: 20 May 2019 / Revised: 5 August 2019 / Accepted: 9 August 2019 / Published online: 20 August 2019 © Springer Nature Switzerland AG 2019

Abstract Epilepsy is one of the most common brain disorders, which can be caused by abnormal synaptic transmissions. Many epilepsy-related mutations have been identifed in synaptic ion channels, which are main targets for current antiepileptic drugs. One of the novel potential targets for therapy of epilepsy is a class of non-ion channel-type epilepsy-related proteins. The leucine-rich repeat glioma-inactivated protein 1 (LGI1) is a neuronal secreted protein, and has been extensively studied as a product of a causative gene for autosomal dominant lateral temporal lobe epilepsy (ADLTE; also known as autosomal dominant partial epilepsy with auditory features [ADPEAF]). At least 43 mutations of LGI1 have been found in ADLTE families. Additionally, autoantibodies against LGI1 in limbic encephalitis are associated with amnesia, seizures, and cognitive dysfunction. Although the relationship of LGI1 with synaptic transmission and synaptic disorders has been studied genetically, biochemically, and clinically, the structural mechanism of LGI1 remained largely unknown until recently. In this review, we introduce insights into pathogenic mechanisms of LGI1 from recent structural studies on LGI1 and its receptor, ADAM22. We also discuss the mechanism for pathogenesis of autoantibodies against LGI1, and the potential of chemical correctors as novel drugs for epilepsy, with structural aspects of LGI1–ADAM22.

Keywords Epilepsy · LGI1 · ADAM22 · Synapse · Autoantibody · Chemical corrector

Introduction receptor, was found to cause autosomal dominant sleep- related hypermotor epilepsy [3, 4], many mutations in ion About 1–2% of the population is sufered from epilepsy. To channel genes have been identifed as epilepsy-related muta- date, over 900 genes have been reported to be associated tions [5, 6]. Therefore, current antiepileptic drugs mainly with epilepsy, and many genetic mutations on these genes target ion channels. Non-ion-channel-type epilepsy-related are directly related to epilepsy [1, 2]. Since a mutation in proteins are another group of drug target for the development CHRNA4, encoding the α4 subunit of nicotinic acetylcholine of new therapeutic strategies for epilepsy. One of the best-characterized non-ion-channel-type epilepsy-related proteins is the leucine-rich repeat glioma- * Atsushi Yamagata inactivated protein 1 (LGI1), which is a neuronal secreted [email protected] protein [7–9]. To date, at least 43 mutations of LGI1 (29 * Shuya Fukai missense mutations and 14 deletion/truncation mutations) [email protected]‑tokyo.ac.jp have been found in autosomal dominant lateral temporal 1 Institute for Quantitative Biosciences, The University lobe epilepsy (ADLTE; also known as autosomal dominant of Tokyo, Tokyo 113‑0032, Japan partial epilepsy with auditory features [ADPEAF]) families 2 Synchrotron Radiation Research Organization, The [7, 10–13]. In addition, autoantibodies against LGI1 in lim- University of Tokyo, Tokyo 113‑0032, Japan bic encephalitis are associated with amnesia, seizures, and 3 Department of Computational Biology and Medical cognitive dysfunction [14–16]. LGI1 knockout mice show Sciences, Graduate School of Frontier Sciences, The severe epileptic phenotype [17–19], which is specifcally res- University of Tokyo, Chiba 277‑8561, Japan cued by the neuronal expression of the LGI1 transgene [18]. 4 Present Address: Laboratory for Protein Functional Genetic, biochemical, and clinical studies have accumulated and Structural Biology, RIKEN Center for Biosystems the evidences of the strong connection between LGI1 and Dynamics Research, Yokohama, Kanagawa 230‑0045, Japan

Vol.:(0123456789)1 3 268 A. Yamagata, S. Fukai epilepsy, and LGI1 has been implicated in brain develop- Pathogenic mutations of LGI1 ment [20–22], neuronal excitability [19, 23, 24], and synaptic transmission [18, 25–27]. However, physiological func- As mentioned above, at least 28 missense mutations have tions of LGI1 still remain elusive. Recent structural studies been reported in patients with familial ADLTE (Table 1). on LGI1 and its receptor, ADAM22 [25], illustrate the trans- Among them, 19 mutations result in secretion-defective synaptic linkage mediated by the higher-order assembly of proteins presumably due to the failure of protein fold- LGI1–ADAM22 and shed light on the relationship between ing [12]. The C42R, C42G, C46R, C46F, C179R, and their mutations and pathogenesis [28]. C200R mutations are mapped onto the cysteine residues forming disulfde bonds in the N- and C-terminal caps of the LRR domain (Fig. 1a) [28], and these mutations LGI1 structure disturb the proper folding. The E383A mutation disrupts the Ca 2+ coordination inside of the β-propeller structure LGI1 is a 60-kDa secreted protein, and predominantly (Fig. 1b, c). In addition, the C286R mutation disrupts the expressed in neuronal cells in the brain [7, 25]. LGI1 con- intra-molecular disulfde bond with Cys260 inside the sists of the N-terminal LRR domain and the C-terminal β-propeller structure (Fig. 1b). A recently found muta- epitempin-repeat (EPTP; also known as EAR) domain [28]. tion, P43R, is located in the N-terminal cap and causes a The structure of LGI1 LRR forms the central fve LRR secretion defect [13]. This mutant LGI1 in cortical neurons repeats, fanked by the N- and C-terminal caps (Fig. 1a). causes dysfunctional cortical neuronal migration, which The C-terminal EPTP domain comprises a seven-bladed might be related to the fact that LGI1-related epilepsies β-propeller, in which each blade is composed of a four- involve mainly the temporal lobe. On the other hand, the stranded antiparallel β-sheet (Fig. 1b). The N-terminal S473L and R474Q mutations are secretion competent strand is assembled with the C-terminal three strands to [12]. The S473L mutation substantially reduces the bind- close the propeller. The EPTP β-propeller structure resem- ing to ADAM22 [12]; whereas, the R474Q mutation disa- bles a WD40 domain. Structural alignment of each blade bles the assembly of the tripartite complex of ADAM22, reveals a WD-like motif, though the position of the WD-like ADAM23, and LGI1 [28]. Structural aspects of this com- motif in LGI1 EPTP is shifted by two residues from those plex are described below. in other canonical WD40 proteins. The unique features of LGI1 EPTP are the disulfde bond inside β-propeller and the coordinated Ca 2+, which stabilize the whole β-propeller structure (Fig. 1b, c).

(a) (b) (c) V432E R407C S473L E383A E383 R474Q T380A R136W I122K C179R D381 A110D I122T C G493R I82T L154P E336 Ca2+ C46R F226C C46F L373S Ca2+ D334 N V382

P43R C286R N C L214P I298T E123K S145R C200R C260 C42R C42G N-cap LRR C-cap L232P F318C

Fig. 1 Domain structures and pathogenic mutations of LGI1. a LGI1 mapped onto the LGI1 EPTP structure. Each blade of the β-propeller LRR structure. Pathogenic mutations are mapped onto the LGI1 LRR is diferently colored. The Ca2+ coordinated inside the β-propeller is structure. The N-cap, LRR, and C-cap regions are colored in light shown as a gray ball. A disulfde bond and N-glycans are shown as gray, light green, and light cyan, respectively. Disulfde bonds are sticks. c The close-up view of the Ca2+ coordination site. Glu383, shown as sticks. b LGI1 EPTP structure. Pathogenic mutations are whose mutation is pathogenic, coordinates Ca2+ via a water molecule

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Table 1 Pathogenic missense Domain Mutation Secretion Efects Reference mutations on LGI1 N-cap C42R − Disruption of the disulfde bond with C48 [11, 12, 36] C42G − Disruption of the disulfde bond with C48 [11, 12, 37] P43R − Misfolding [13] C46R − Disruption of the disulfde bond with C55 [11, 12, 38, 39] C46F N.E. Disruption of the disulfde bond with C55 [40] LRR I82T N.E. Misfolding [41] A110D − Misfolding [11, 12, 36] I122K − Misfolding [11, 12, 42] I122T − Misfolding [12, 43] E123K − Misfolding [11, 12, 42, 44] R136W − Misfolding [11, 12, 42, 43] S145R − Misfolding [11, 12, 45] L154P − Misfolding [11, 12, 46] C-cap C179R − Disruption of the disulfde bond with C221 [12, 43] C200R − Disruption of the disulfde bond with C177 [11, 12, 47] L214P N.E. Misfolding [48] EPTP F226C N.E. Misfolding [49] L232P − Misfolding [11, 12, 50] C286R N.E. Disruption of the disulfde bond with C260 [51] I298T − Misfolding [11, 12, 36] F318C − Misfolding [11, 12, 52] L373S N.E. Misfolding [51] T380A − Misfolding [12, 53] E383A − Misfolding [7, 11, 12] R407C + unafected [12, 28, 54] V432E − Misfolding [11, 12, 47] S473L + Disruption of the binding to ADAM22 [11, 12, 37, 49] R474Q + Disruption of LGI1–LGI1 interaction [12, 24, 28, 55] G493R − Misfolding [12, 56]

ADAM22 and other ADAM22 family proteins Mechanisms of the interaction between LGI1 and ADAM22 ADAM22 has been identifed as a receptor of LGI1 [25]. The LGI1–ADAM22 complex plays a critical role in The EPTP domain of LGI1 is sufficient for binding AMPA receptor-mediated synaptic transmission [18, 25, to ADAM22 [25]. The crystal structure of the LGI1 29]. ADAM22 belongs to a transmembrane ADAM met- EPTP–ADAM22 complex reveals that LGI1 EPTP binds alloprotease family [30]. However, the histidine residues to the metalloprotease domain of ADAM22 (Fig. 2a) [28]. coordinating the catalytic zinc ion are replaced with other Three aromatic residues in ADAM22 (Trp398, Tyr408, and residues in ADAM22 [31]. To our knowledge, it is likely Tyr409 in human ADAM22) stick into a hydrophobic pocket that ADAM22 solely functions as a receptor for LGI1 [25]. located at the rim of the EPTP propeller (Fig. 2b). Mutations ADAM22 is translated as a premature form including the in the binding interface disturb the interaction between LGI1 propeptide, and converted into a mature form by its cleav- and ADAM22 [28]. Similar mutations also disturb the inter- age [31]. The extracellular domain of the mature form of action between LGI1 and ADAM23, suggesting that LGI1 ADAM22 is composed of a metalloprotease-like domain, a binds to ADAM22 and ADAM23 in a similar manner [28]. disintegrin domain, a cysteine-rich domain and an epidermal The structure of the binding interface explains the patho- growth factor (EGF)-like domain (Fig. 2a) [28, 31]. Afnity genic mechanism of the C401Y mutation in ADAM22, purifcation of the LGI1-containing complex from mouse which has been found in a patient with rapidly progressing brain expressing LGI1 fused with FLAG and His 6 tags dem- severe encephalopathy with intractable seizures and pro- onstrated that LG1 binds to other ADAM22-family proteins, found intellectual disability [32]. The three aromatic resi- ADAM23 and ADAM11, as well as ADAM22 [18]. dues of ADAM22 undergo the conformational change upon

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Fig. 2 Structure of the LGI1 (a) (b) EPTP–ADAM22 complex. a LGI1 EPTP Crystal structure of the LGI1 C Y409 EPTP–ADAM22 complex. LGI1 EPTP N W398 Y408 LGI1 EPTP is colored green. A metalloprotease-like domain, a disintegrin domain, a cysteine- rich domain, and an epidermal growth factor (EGF)-like domain in ADAM22 are colored in purple, hot pink, pink, and gray, respectively. Disulfde bonds and N-glycans are shown C401 as sticks. b Close-up view of Metalloprotease-like the binding interface. The side C394 chains of Trp398, Tyr408, and ADAM22 Tyr409 and the disulfde bond between Cys394 and Cys401 are shown as sticks. LGI1 EPTP is shown as a surface model

Cysteine-rich Disintegrin

EGF-like ADAM22 binding to LGI1 [28]. The disulfde bond formed between is defective in secretion, whereas LGI1R474Q can be nor- Cys394 and Cys401 appears to support this conformational mally secreted from transfected HEK293T cells and bind to change (Fig. 2b). A defect in this disulfde bond impairs the ADAM22 [12, 28]. A pathogenic R474Q mutation of LGI1 binding of ADAM22 to LGI1 [32]. These structural data disrupts the higher-order assembly of the LGI1–ADAM22 reinforce the notion that the disruption of LGI1–ADAM22 complex [28]. Moreover, LGI1R474Q could not rescue the interaction causes epilepsy, which has been supported by epileptic phenotype of LGI1 knockout mice [28]. These clinical and biochemical studies. fndings indicate that the disruption of the higher-order assembly of the LGI1–ADAM22 complex is directly linked to pathogenesis. Higher‑order assembly of the LGI1–ADAM22 complex LGI1–ADAM22 forms a synaptic protein The crystal structure of the full-length LGI1 in complex with network ADAM22 exhibits a 2:2 heterotetramer in a dimer-of-dimer assembly (Fig. 3a) [28]. The LRR domain of one LGI1 mol- As mentioned above, LGI1 has been suggested to form a ecule interacts with the EPTP domain of the other LGI1 complex with ADAM22, ADAM23, and ADAM11 in mouse molecule, thereby bridging two distant ADAM22 molecules. brain [18]. In addition to the ADAM22 family members, var- There are no observed interactions between the two LGI1 ious synaptic proteins were also included in the LGI1 com- LRRs in the 2:2 LGI1–ADAM22 complex. Size-exclusion plex. Such synaptic proteins involve postsynaptic scafolding chromatography-coupled multiangle light scattering (SEC- proteins (PSD-95, PSD-93, and SAP97), presynaptic scaf- MALS) and small angle X-ray scattering (SEC-SAXS), and folding proteins (CASK and Lin7), and a potassium chan- cryo-electron microscopy (cryo-EM) suggest the presence of nel [18, 25, 27]. ADAM22 binds to the third PDZ domain the 3:3 heterohexamer in solution besides the 2:2 heterote- in PSD-95 via its C-terminal PDZ-binding motif [25, 29]. tramer (Fig. 3b) [28]. Two human ADLTE mutations, E123K PSD-95 binds to a stargazin–AMPA receptor complex via and R474Q, are located in the interface of the LGI1–LGI1 the frst and second PDZ domains [33, 34]. Through this interaction in the 2:2 assembly of the LGI1–ADAM22 com- synaptic protein network, LGI1 modulates AMPA receptor- plex (and also likely the 3:3 assembly) (Fig. 3c). LGI1E123K mediated synaptic transmission.

1 3 271 Insights into the mechanisms of epilepsy from structural biology of LGI1–ADAM22

(a) (b) (d)

ADAM22 LGI1 Presynapse LGI1 ADAM22 Lin7

LGI1 EPTP Kv1 Kv1 LGI1 ADAM23 ADAM22 ADAM22

LGI1 LRR LGI1 LGI1 190

LGI1 LRR AMPA-R

ADAM22 n (c) LGI1 LRR Postsynapse LGI1 EPTP

R474 Stargazi Stargazin PSD95 ADAM22 E123

LGI1 EPTP

(e)

Myelinating cell

Caspr2 LGI1 ADAM22 LGI1 ADAM22 TAG-1 ADAM22 TAG-1 LGI1

Kv1 Kv1 Kv1 Kv1

PSD95 PSD95 Axon

Fig. 3 Higher-order assembly of the LGI1–ADAM22 complex. a SEC-SAXS analysis of the complex. c Close-up view of the LGI1– Crystal structure of the LGI1–ADAM22 complex. The full-length LGI1 interface. d Model of the transsynaptic linkage through the LGI1 and ADAM22 forms a 2:2 heterotetrameric complex through tripartite complex of ADAM22–(LGI1)2–ADAM23 at the excitatory the LGI1–LGI1 interaction. b The 3:3 assembly model of the LGI1– synapse. e Model of the 3:3 LGI1–ADAM22 complex at the axon ini- ADAM22 complex (top), based on a cryo-EM image (bottom) and tial segment

1 3 272 A. Yamagata, S. Fukai

The higher-order assembly of the LGI1–ADAM22 New therapeutic options for epilepsy complex is consistent with the physical and functional transsynaptic linkage through the tripartite complex of As noted above, most of the LGI1 mutants are defective in LGI1, ADAM22 and ADAM23 in synapses, although secretion. For example, LGI1E383A, whose EPTP β-propeller the LGI1–ADAM22 complex may act in a cis fashion is defective in the Ca 2+ coordination, is captured by the ER on the postsynaptic membrane. The longest axis of the quality-control machinery and prematurely degraded [12]. 2:2 LGI1–ADAM22 assembly from the crystal structure To restore the conformation and function of LGI1 mutants, is about 190 Å, which is comparable to the size of the a chemical corrector, 4-phenylbutylate (4PBA), was tested excitatory synaptic cleft (Fig. 3a). Assuming that one [12]. The 4PBA treatment signifcantly improved the secre- molecule of ADAM22 in the 2:2 LGI1–ADAM22 mim- tion of LGI1 mutants and their binding to ADAM22. The −/− ics ADAM23, the tripartite ADAM22–(LGI1)2–ADAM23 4PBA treatment slightly improved the lethality of LGI1 ; complex can be modeled (Fig. 3d). The tripartite complex E384A transgenic mice, and greatly reduced the number of formation can be verifed by immunoprecipitation of either mice displaying spontaneous generalized seizures. Although ADAM22 or ADAM23 from mouse brain [28]. Impor- 4PBA treatment could not perfectly rescue LGI1 mutant R474Q tantly, LGI1 disturbs the tripartite complex formation mice, small molecules serving as chemical correctors might in mouse brain [28]. Further biophysical and/or structural be new therapeutic options for LGI1-mediated epilepsy. data that directly confrm the presence of the transsynaptic Acknowledgements ADAM22–(LGI1)2–ADAM23 complex are awaited. The research in SF’s lab has been supported On the other hand, recent studies have reported that by Grants from JSPS/MEXT KAKENHI (JP16H04749 to A.Y. and JP24247014 and JP18H03983 to S.F.) and JST CREST (JPM- LGI1 is enriched at the axon initial segment and colocal- JCR12M5) to S.F. We apologize to colleagues whose research could ized with ADAM22/23 and the voltage-gated potassium not be cited due to space limitation. (Kv1) channels [23, 24]. Kv1-associated cell-adhesion molecules, TAG-1 and Caspr2, likely mediate this colocal- Compliance with ethical standards ization by binding to ADAM22/23 [24]. LGI1 knock-out mice exhibit a decrease in the density of the Kv1 channels, Conflict of interest The authors declare that they have no competing which is related to an increased neuronal excitability of interests. hippocampal CA3 neurons. LGI1R474Q disturbs the colo- calization of ADAM22/23 and the Kv1 channels [24]. In this context, the 3:3 LGI1–ADAM22 complex observed References in vitro might facilitate efcient clustering of the axonal Kv1 channels to control their density and inhibit epilepsy 1. Fukata Y, Fukata M (2017) Epilepsy and synaptic pro- (Fig. 3e). teins. Curr Opin Neurobiol 45:1–8. https://doi.org/10.1016/j. conb.2017.02.001 2. Steinlein OK (2004) Genetic mechanisms that underlie epilepsy. Nat Rev Neurosci 5(5):400–408. https://doi.org/10.1038/nrn13 88 Autoantibodies against LGI1 3. Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, Schefer IE, Berkovic SF (1995) A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subu- Autoantibodies against LGI1 have been described in patients nit is associated with autosomal dominant nocturnal frontal lobe with a class of limbic encephalitis and cause acquired neu- epilepsy. Nat Genet 11(2):201–203. https://doi.org/10.1038/ng109 5-201 romyotonia, seizures, and memory loss [14–16]. At the 4. Tinuper P, Bisulli F, Cross JH, Hesdorfer D, Kahane P, Nobili L, molecular level, the autoantibodies from patients specif- Provini F, Schefer IE, Tassi L, Vignatelli L, Bassetti C, Cirignotta cally recognize the LRR and EPTP domains of LGI1, and F, Derry C, Gambardella A, Guerrini R, Halasz P, Licchetta L, block the LGI1–ADAM22/ADAM23 assembly [26, 35]. Mahowald M, Manni R, Marini C, Mostacci B, Naldi I, Parrino L, Picard F, Pugliatti M, Ryvlin P, Vigevano F, Zucconi M, Berkovic In cultured neurons or in the hippocampus after passive S, Ottman R (2016) Defnition and diagnostic criteria of sleep- transfer to mice, the autoantibodies decreased the levels of related hypermotor epilepsy. Neurology 86(19):1834–1842. https both presynaptic Kv1.1 channel clusters and postsynaptic ://doi.org/10.1212/WNL.0000000000002666 AMPA receptor clusters, resulting in increased presynaptic 5. Wei F, Yan LM, Su T, He N, Lin ZJ, Wang J, Shi YW, Yi YH, Liao WP (2017) Ion channel genes and epilepsy: functional altera- release and enhancement of glutamatergic synaptic transmis- tion, pathogenic potential, and mechanism of epilepsy. Neurosci sion [26, 35]. The efects on both the presynaptic and post- Bull 33(4):455–477. https://doi.org/10.1007/s12264-017-0134-1 synaptic functions suggest that the autoantibodies disturb 6. Oyrer J, Maljevic S, Schefer IE, Berkovic SF, Petrou S, Reid CA the transsynaptic linkage through the LGI1–ADAM22/23 (2018) Ion channels in genetic epilepsy: from genes and mechanisms to disease-targeted therapies. Pharmacol Rev 70(1):142– assembly by inhibiting the interaction between LGI1 and 173. https://doi.org/10.1124/pr.117.014456 ADAM22/23.

1 3 273 Insights into the mechanisms of epilepsy from structural biology of LGI1–ADAM22

7. Kalachikov S, Evgrafov O, Ross B, Winawer M, Barker-Cum- 21. Thomas R, Favell K, Morante-Redolat J, Pool M, Kent C, mings C, Martinelli Boneschi F, Choi C, Morozov P, Das K, Wright M, Daignault K, Ferraro GB, Montcalm S, Durocher Y, Teplitskaya E, Yu A, Cayanis E, Penchaszadeh G, Kottmann Fournier A, Perez-Tur J, Barker PA (2010) LGI1 is a Nogo recep- AH, Pedley TA, Hauser WA, Ottman R, Gilliam TC (2002) tor 1 ligand that antagonizes myelin-based growth inhibition. J Mutations in LGI1 cause autosomal-dominant partial epilepsy Neurosci 30(19):6607–6612. https://doi.org/10.1523/JNEUR with auditory features. Nat Genet 30(3):335–341. https://doi. OSCI.5147-09.2010 org/10.1038/ng832 22. Zhou YD, Zhang D, Ozkaynak E, Wang X, Kasper EM, Leguern 8. Senechal KR, Thaller C, Noebels JL (2005) ADPEAF mutations E, Baulac S, Anderson MP (2012) Epilepsy gene LGI1 regulates reduce levels of secreted LGI1, a putative tumor suppressor pro- postnatal developmental remodeling of retinogeniculate syn- tein linked to epilepsy. Hum Mol Genet 14(12):1613–1620. https apses. J Neurosci 32(3):903–910. https://doi.org/10.1523/JNEUR ://doi.org/10.1093/hmg/ddi169 OSCI.5191-11.2012 9. Fukata Y, Yokoi N, Miyazaki Y, Fukata M (2017) The LGI1- 23. Seagar M, Russier M, Caillard O, Maulet Y, Fronzaroli-Molinieres ADAM22 protein complex in synaptic transmission and synaptic L, De San Feliciano M, Boumedine-Guignon N, Rodriguez L, disorders. Neurosci Res 116:39–45. https://doi.org/10.1016/j. Zbili M, Usseglio F, Formisano-Treziny C, Youssouf F, Sangiardi neures.2016.09.011 M, Boillot M, Baulac S, Benitez MJ, Garrido JJ, Debanne D, 10. Rosanof MJ, Ottman R (2008) Penetrance of LGI1 mutations El Far O (2017) LGI1 tunes intrinsic excitability by regulating in autosomal dominant partial epilepsy with auditory features. the density of axonal Kv1 channels. Proc Natl Acad Sci USA Neurology 71(8):567–571. https://doi.org/10.1212/01.wnl.00003 114(29):7719–7724. https://doi.org/10.1073/pnas.1618656114 23926.77565.ee 24. Hivert B, Marien L, Agbam KN, Faivre-Sarrailh C (2019) 11. Nobile C, Michelucci R, Andreazza S, Pasini E, Tosatto SC, Stri- ADAM22 and ADAM23 modulate the targeting of the Kv1 chan- ano P (2009) LGI1 mutations in autosomal dominant and sporadic nel-associated protein LGI1 to the axon initial segment. J Cell Sci lateral temporal epilepsy. Hum Mutat 30(4):530–536. https://doi. 132:2. https://doi.org/10.1242/jcs.219774 org/10.1002/humu.20925 25. Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA, 12. Yokoi N, Fukata Y, Kase D, Miyazaki T, Jaegle M, Ohkawa T, Fukata M (2006) Epilepsy-related ligand/receptor complex Takahashi N, Iwanari H, Mochizuki Y, Hamakubo T, Imoto K, LGI1 and ADAM22 regulate synaptic transmission. Science Meijer D, Watanabe M, Fukata M (2015) Chemical corrector 313(5794):1792–1795. https://doi.org/10.1126/science.1129947 treatment ameliorates increased seizure susceptibility in a mouse 26. Ohkawa T, Fukata Y, Yamasaki M, Miyazaki T, Yokoi N, model of familial epilepsy. Nat Med 21(1):19–26. https://doi. Takashima H, Watanabe M, Watanabe O, Fukata M (2013) org/10.1038/nm.3759 Autoantibodies to epilepsy-related LGI1 in limbic encephali- 13. Liu F, Du C, Tian X, Ma Y, Zhao B, Yan Y, Lin Z, Lin P, Zhou R, tis neutralize LGI1–ADAM22 interaction and reduce synaptic Wang X (2019) A novel LGI1 missense mutation causes dysfunc- AMPA receptors. J Neurosci 33(46):18161–18174. https://doi. tion in cortical neuronal migration and seizures. Brain Res. https org/10.1523/JNEUROSCI.3506-13.2013 ://doi.org/10.1016/j.brainres.2019.146332 27. Schulte U, Thumfart JO, Klocker N, Sailer CA, Bildl W, Biniossek 14. Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani M, Dehn D, Deller T, Eble S, Abbass K, Wangler T, Knaus L, Peles E, Buckley C, Lang B, Vincent A (2010) Antibodies HG, Fakler B (2006) The epilepsy-linked Lgi1 protein assem- to Kv1 potassium channel-complex proteins leucine-rich, glioma bles into presynaptic Kv1 channels and inhibits inactivation by inactivated 1 protein and contactin-associated protein-2 in limbic Kvbeta1. Neuron 49(5):697–706. https://doi.org/10.1016/j.neuro encephalitis, Morvan’s syndrome and acquired neuromyotonia. n.2006.01.033 Brain 133(9):2734–2748. https://doi.org/10.1093/brain/awq213 28. Yamagata A, Miyazaki Y, Yokoi N, Shigematsu H, Sato Y, Goto- 15. Lai M, Huijbers MG, Lancaster E, Graus F, Bataller L, Balice- Ito S, Maeda A, Goto T, Sanbo M, Hirabayashi M, Shirouzu M, Gordon R, Cowell JK, Dalmau J (2010) Investigation of LGI1 as Fukata Y, Fukata M, Fukai S (2018) Structural basis of epilepsy- the antigen in limbic encephalitis previously attributed to potas- related ligand-receptor complex LGI1–ADAM22. Nat Commun sium channels: a case series. Lancet Neurol 9(8):776–785. https 9(1):1546. https://doi.org/10.1038/s41467-018-03947-w ://doi.org/10.1016/S1474-4422(10)70137-X 29. Lovero KL, Fukata Y, Granger AJ, Fukata M, Nicoll RA (2015) 16. van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ (2017) The LGI1-ADAM22 protein complex directs synapse maturation The value of LGI1, Caspr2 and voltage-gated potassium channel through regulation of PSD-95 function. Proc Natl Acad Sci USA antibodies in encephalitis. Nat Rev Neurol 13(5):290–301. https 112(30):E4129–E4137. https://doi.org/10.1073/pnas.15119 10112 ://doi.org/10.1038/nrneurol.2017.43 30. Sagane K, Ohya Y, Hasegawa Y, Tanaka I (1998) Metallopro- 17. Chabrol E, Navarro V, Provenzano G, Cohen I, Dinocourt C, teinase-like, disintegrin-like, cysteine-rich proteins MDC2 and Rivaud-Pechoux S, Fricker D, Baulac M, Miles R, Leguern E, MDC3: novel human cellular disintegrins highly expressed in the Baulac S (2010) Electroclinical characterization of epileptic sei- brain. Biochem J 334(Pt 1):93–98 zures in leucine-rich, glioma-inactivated 1-defcient mice. Brain 31. Liu H, Shim AH, He X (2009) Structural characterization of the 133(9):2749–2762. https://doi.org/10.1093/brain/awq171 ectodomain of a disintegrin and metalloproteinase-22 (ADAM22), 18. Fukata Y, Lovero KL, Iwanaga T, Watanabe A, Yokoi N, Tabu- a neural adhesion receptor instead of metalloproteinase: insights chi K, Shigemoto R, Nicoll RA, Fukata M (2010) Disruption of on ADAM function. J Biol Chem 284(42):29077–29086. https:// LGI1-linked synaptic complex causes abnormal synaptic trans- doi.org/10.1074/jbc.M109.014258 mission and epilepsy. Proc Natl Acad Sci USA 107(8):3799–3804. 32. Muona M, Fukata Y, Anttonen AK, Laari A, Palotie A, Pihko https://doi.org/10.1073/pnas.0914537107 H, Lonnqvist T, Valanne L, Somer M, Fukata M, Lehesjoki 19. Yu YE, Wen L, Silva J, Li Z, Head K, Sossey-Alaoui K, Pao A, AE (2016) Dysfunctional ADAM22 implicated in progressive Mei L, Cowell JK (2010) Lgi1 null mutant mice exhibit myo- encephalopathy with cortical atrophy and epilepsy. Neurol Genet clonic seizures and CA1 neuronal hyperexcitability. Hum Mol 2(1):e46. https://doi.org/10.1212/NXG.0000000000000046 Genet 19(9):1702–1711. https://doi.org/10.1093/hmg/ddq047 33. Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki 20. Zhou YD, Lee S, Jin Z, Wright M, Smith SE, Anderson MP (2009) Y, Wenthold RJ, Bredt DS, Nicoll RA (2000) Stargazin regulates Arrested maturation of excitatory synapses in autosomal dominant synaptic targeting of AMPA receptors by two distinct mecha- lateral temporal lobe epilepsy. Nat Med 15(10):1208–1214. https nisms. Nature 408(6815):936–943. https://doi.org/10.1038/35050 ://doi.org/10.1038/nm.2019 030

1 3 274 A. Yamagata, S. Fukai

34. Sainlos M, Tigaret C, Poujol C, Olivier NB, Bard L, Breillat C, 47. Michelucci R, Poza JJ, Sofa V, de Feo MR, Binelli S, Bisulli Thiolon K, Choquet D, Imperiali B (2011) Biomimetic divalent F, Scudellaro E, Simionati B, Zimbello R, D’Orsi G, Passarelli ligands for the acute disruption of synaptic AMPAR stabilization. D, Avoni P, Avanzini G, Tinuper P, Biondi R, Valle G, Mautner Nat Chem Biol 7(2):81–91. https://doi.org/10.1038/nchem bio.498 VF, Stephani U, Tassinari CA, Moschonas NK, Siebert R, Lopez 35. Petit-Pedrol M, Sell J, Planaguma J, Mannara F, Radosevic M, de Munain A, Perez-Tur J, Nobile C (2003) Autosomal domi- Haselmann H, Ceanga M, Sabater L, Spatola M, Soto D, Gasull X, nant lateral temporal epilepsy: clinical spectrum, new epitempin Dalmau J, Geis C (2018) LGI1 antibodies alter Kv1.1 and AMPA mutations, and genetic heterogeneity in seven European families. receptors changing synaptic excitability, plasticity and memory. Epilepsia 44(10):1289–1297 Brain 141(11):3144–3159. https://doi.org/10.1093/brain /awy25 3 48. Klein KM, Pendziwiat M, Cohen R, Appenzeller S, de Kovel CG, 36. Ottman R, Winawer MR, Kalachikov S, Barker-Cummings C, Rosenow F, Koeleman BP, Kuhlenbaumer G, Sheintuch L, Vek- Gilliam TC, Pedley TA, Hauser WA (2004) LGI1 mutations in sler R, Friedman A, Afawi Z, Helbig I (2016) Autosomal domi- autosomal dominant partial epilepsy with auditory features. Neu- nant epilepsy with auditory features: a new LGI1 family including rology 62(7):1120–1126 a phenocopy with cortical dysplasia. J Neurol 263(1):11–16. https 37. Berkovic SF, Izzillo P, McMahon JM, Harkin LA, McIntosh AM, ://doi.org/10.1007/s00415-015-7921-2 Phillips HA, Briellmann RS, Wallace RH, Mazarib A, Neufeld 49. Fumoto N, Matsumoto R, Kawamata J, Koyasu S, Kondo T, MY, Korczyn AD, Schefer IE, Mulley JC (2004) LGI1 mutations Kitamura A, Koshiba Y, Kinoshita M, Kawasaki J, Yamashita H, in temporal lobe epilepsies. Neurology 62(7):1115–1119 Takahashi R, Ikeda A (2017) Novel LGI1 mutation in a Japanese 38. Gu W, Brodtkorb E, Steinlein OK (2002) LGI1 is mutated in autosomal dominant lateral temporal lobe epilepsy family. Neurol familial temporal lobe epilepsy characterized by aphasic seizures. Clin Neurosci 5(1):44–45. https://doi.org/10.1111/ncn3.12105 Ann Neurol 52(3):364–367. https://doi.org/10.1002/ana.10280 50. Chabrol E, Popescu C, Gourfnkel-An I, Trouillard O, Depienne 39. Pizzuti A, Flex E, Di Bonaventura C, Dottorini T, Egeo G, C, Senechal K, Baulac M, LeGuern E, Baulac S (2007) Two Manfredi M, Dallapiccola B, Giallonardo AT (2003) Epilepsy novel epilepsy-linked mutations leading to a loss of function of with auditory features: a LGI1 gene mutation suggests a loss- LGI1. Arch Neurol 64(2):217–222. https://doi.org/10.1001/archn of-function mechanism. Ann Neurol 53(3):396–399. https://doi. eur.64.2.217 org/10.1002/ana.10492 51. Dazzo E, Santulli L, Posar A, Fattouch J, Conti S, Loden-van 40. Lee MK, Kim SW, Lee JH, Cho YJ, Kim DE, Lee BI, Kim HM, Straaten M, Mijalkovic J, De Bortoli M, Rosa M, Millino C, Pac- Lee MG, Heo K (2014) A newly discovered LGI1 mutation in chioni B, Di Bonaventura C, Giallonardo AT, Striano S, Striano Korean family with autosomal dominant lateral temporal lobe P, Parmeggiani A, Nobile C (2015) Autosomal dominant lateral epilepsy. Seizure 23(1):69–73. https://doi.org/10.1016/j.seizu temporal epilepsy (ADLTE): novel structural and single-nucleo- re.2013.10.001 tide LGI1 mutations in families with predominant visual auras. 41. Sadleir LG, Agher D, Chabrol E, Elkouby L, Leguern E, Pater- Epilepsy Res 110:132–138. https://doi.org/10.1016/j.eplepsyres son SJ, Harty R, Bellows ST, Berkovic SF, Schefer IE, Baulac S .2014.12.004 (2013) Seizure semiology in autosomal dominant epilepsy with 52. Fertig E, Lincoln A, Martinuzzi A, Mattson RH, Hisama auditory features, due to novel LGI1 mutations. Epilepsy Res FM (2003) Novel LGI1 mutation in a family with autosomal 107(3):311–317. https://doi.org/10.1016/j.eplep syres .2013.09.008 dominant partial epilepsy with auditory features. Neurology 42. Striano P, de Falco A, Diani E, Bovo G, Furlan S, Vitiello L, 60(10):1687–1690 Pinardi F, Striano S, Michelucci R, de Falco FA, Nobile C (2008) 53. Leonardi E, Andreazza S, Vanin S, Busolin G, Nobile C, Tosatto A novel loss-of-function LGI1 mutation linked to autosomal SC (2011) A computational model of the LGI1 protein suggests a dominant lateral temporal epilepsy. Arch Neurol 65(7):939–942. common binding site for ADAM proteins. PLoS One 6(3):e18142. https://doi.org/10.1001/archneur.65.7.939 https://doi.org/10.1371/journal.pone.0018142 43. Di Bonaventura C, Operto FF, Busolin G, Egeo G, D’Aniello A, 54. Striano P, Busolin G, Santulli L, Leonardi E, Coppola A, Vitiello Vitello L, Smaniotto G, Furlan S, Diani E, Michelucci R, Gial- L, Rigon L, Michelucci R, Tosatto SC, Striano S, Nobile C (2011) lonardo AT, Coppola G, Nobile C (2011) Low penetrance and Familial temporal lobe epilepsy with psychic auras associated efect on protein secretion of LGI1 mutations causing autosomal with a novel LGI1 mutation. Neurology 76(13):1173–1176. https dominant lateral temporal epilepsy. Epilepsia 52(7):1258–1264. ://doi.org/10.1212/WNL.0b013e318212ab2e https://doi.org/10.1111/j.1528-1167.2011.03071.x 55. Kawamata J, Ikeda A, Fujita Y, Usui K, Shimohama S, Takahashi 44. Di Bonaventura C, Carni M, Diani E, Fattouch J, Vaudano EA, R (2010) Mutations in LGI1 gene in Japanese families with auto- Egeo G, Pantano P, Maraviglia B, Bozzao L, Manfredi M, Prenc- somal dominant lateral temporal lobe epilepsy: the frst report ipe M, Giallonardo TA, Nobile C (2009) Drug resistant ADLTE from Asian families. Epilepsia 51(4):690–693. https://doi.org/10 and recurrent partial status epilepticus with dysphasic features in .1111/j.1528-1167.2009.02309.x a family with a novel LGI1 mutation: electroclinical, genetic, and 56. Heiman GA, Kamberakis K, Gill R, Kalachikov S, Pedley TA, EEG/fMRI fndings. Epilepsia 50(11):2481–2486. https://doi.org Hauser WA, Ottman R (2010) Evaluation of depression risk in /10.1111/j.1528-1167.2009.02181.x LGI1 mutation carriers. Epilepsia 51(9):1685–1690. https://doi. 45. Hedera P, Abou-Khalil B, Crunk AE, Taylor KA, Haines JL, Sut- org/10.1111/j.1528-1167.2010.02677.x clife JS (2004) Autosomal dominant lateral temporal epilepsy: two families with novel mutations in the LGI1 gene. Epilepsia Publisher’s Note Springer Nature remains neutral with regard to 45(3):218–222 jurisdictional claims in published maps and institutional afliations. 46. Pisano T, Marini C, Brovedani P, Brizzolara D, Pruna D, Mei D, Moro F, Cianchetti C, Guerrini R (2005) Abnormal phonologic processing in familial lateral temporal lobe epilepsy due to a new LGI1 mutation. Epilepsia 46(1):118–123. https://doi.org/10.111 1/j.0013-9580.2005.26304.x

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