A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions
Autoři:
Pierre Coste de Bagneaux aff001; Leonie von Elsner aff002; Tatjana Bierhals aff002; Marta Campiglio aff001; Jessika Johannsen aff003; Gerald J. Obermair aff001; Maja Hempel aff002; Bernhard E. Flucher aff001; Kerstin Kutsche aff002
Působiště autorů:
Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Austria
aff001; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
aff002; Childrens Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
aff003; Division Physiology, Karl Landsteiner University of Health Sciences, Krems, Austria
aff004
Vyšlo v časopise:
A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008625
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008625
Souhrn
P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming CaV2.1 α1 subunit and the auxiliary α2δ-2 and β4 subunits. β4 is encoded by CACNB4, and its multiple splice variants serve isoform-specific functions as channel subunits and transcriptional regulators in the nucleus. In two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy we identified rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. In silico tools, animal model, clinical, and genetic data suggest the p.(Leu126Pro) CACNB4 variant to be likely pathogenic. To investigate the functional consequences of the CACNB4 variant, we introduced the corresponding mutation L125P into rat β4b cDNA. Heterologously expressed wild-type β4b associated with GFP-CaV1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the β4b-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with CaV2.1 in tsA201 cells, β4b and β4b-L125P augmented the calcium current amplitudes, however, β4b-L125P failed to stably complex with α1 subunits. These results indicate that p.Leu125Pro disrupts the stable association of β4b with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype β4b was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of β4b in cultured myotubes and hippocampal neurons. While binding of β4b to the known interaction partner PPP2R5D (B56δ) was not affected by the mutation, complex formation between β4b-L125P and the neuronal TRAF2 and NCK interacting kinase (TNIK) seemed to be disturbed. In summary, our data suggest that the homozygous CACNB4 p.(Leu126Pro) variant underlies the severe neurological phenotype in the two siblings, most likely by impairing both channel and non-channel functions of β4b.
Klíčová slova:
Atrophy – Axons – Calcium channels – Co-immunoprecipitation – Epilepsy – Immunoprecipitation – Mouse models – Neurons
Zdroje
1. Catterall WA, Few AP. Calcium channel regulation and presynaptic plasticity. Neuron. 2008;59(6):882–901. doi: 10.1016/j.neuron.2008.09.005 18817729.
2. Wittemann S, Mark MD, Rettig J, Herlitze S. Synaptic localization and presynaptic function of calcium channel beta 4-subunits in cultured hippocampal neurons. J Biol Chem. 2000;275(48):37807–14. doi: 10.1074/jbc.M004653200 10931840.
3. Randall A, Tsien RW. Pharmacological dissection of multiple types of Ca2+ channel currents in rat cerebellar granule neurons. J Neurosci. 1995;15(4):2995–3012. doi: 10.1523/JNEUROSCI.15-04-02995.1995 7722641.
4. Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011;3(8):a003947. doi: 10.1101/cshperspect.a003947 21746798; PubMed Central PMCID: PMC3140680.
5. Schlick B, Flucher BE, Obermair GJ. Voltage-activated calcium channel expression profiles in mouse brain and cultured hippocampal neurons. Neuroscience. 2010;167(3):786–98. doi: 10.1016/j.neuroscience.2010.02.037 20188150; PubMed Central PMCID: PMC3315124.
6. Pagani R, Song M, McEnery M, Qin N, Tsien RW, Toro L, et al. Differential expression of alpha 1 and beta subunits of voltage dependent Ca2+ channel at the neuromuscular junction of normal and P/Q Ca2+ channel knockout mouse. Neuroscience. 2004;123(1):75–85. doi: 10.1016/j.neuroscience.2003.09.019 14667443.
7. Arikkath J, Campbell KP. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr Opin Neurobiol. 2003;13(3):298–307. doi: 10.1016/s0959-4388(03)00066-7 12850214.
8. Campiglio M, Flucher BE. The role of auxiliary subunits for the functional diversity of voltage-gated calcium channels. J Cell Physiol. 2015;230(9):2019–31. doi: 10.1002/jcp.24998 25820299; PubMed Central PMCID: PMC4672716.
9. Buraei Z, Yang J. The ss subunit of voltage-gated Ca2+ channels. Physiol Rev. 2010;90(4):1461–506. doi: 10.1152/physrev.00057.2009 20959621; PubMed Central PMCID: PMC4353500.
10. Geisler S, Schopf CL, Obermair GJ. Emerging evidence for specific neuronal functions of auxiliary calcium channel alpha(2)delta subunits. Gen Physiol Biophys. 2015;34(2):105–18. doi: 10.4149/gpb_2014037 25504062; PubMed Central PMCID: PMC4487825.
11. Geisler S, Schopf CL, Stanika R, Kalb M, Campiglio M, Repetto D, et al. Presynaptic alpha2delta-2 Calcium Channel Subunits Regulate Postsynaptic GABAA Receptor Abundance and Axonal Wiring. J Neurosci. 2019;39(14):2581–605. doi: 10.1523/JNEUROSCI.2234-18.2019 30683685; PubMed Central PMCID: PMC6445987.
12. Imbrici P, Jaffe SL, Eunson LH, Davies NP, Herd C, Robertson R, et al. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain. 2004;127(Pt 12):2682–92. doi: 10.1093/brain/awh301 15483044.
13. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997;15(1):62–9. doi: 10.1038/ng0197-62 8988170.
14. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996;87(3):543–52. doi: 10.1016/s0092-8674(00)81373-2 8898206.
15. Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000;66(5):1531–9. doi: 10.1086/302909 10762541; PubMed Central PMCID: PMC1378014.
16. Barclay J, Balaguero N, Mione M, Ackerman SL, Letts VA, Brodbeck J, et al. Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. J Neurosci. 2001;21(16):6095–104. doi: 10.1523/JNEUROSCI.21-16-06095.2001 11487633.
17. Jun K, Piedras-Renteria ES, Smith SM, Wheeler DB, Lee SB, Lee TG, et al. Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit. Proc Natl Acad Sci U S A. 1999;96(26):15245–50. doi: 10.1073/pnas.96.26.15245 10611370; PubMed Central PMCID: PMC24805.
18. Fletcher CF, Tottene A, Lennon VA, Wilson SM, Dubel SJ, Paylor R, et al. Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity. FASEB J. 2001;15(7):1288–90. doi: 10.1096/fj.00-0562fje 11344116.
19. Khan Z, Jinnah HA. Paroxysmal dyskinesias in the lethargic mouse mutant. J Neurosci. 2002;22(18):8193–200. doi: 10.1523/JNEUROSCI.22-18-08193.2002 12223573.
20. Pietrobon D. Function and dysfunction of synaptic calcium channels: insights from mouse models. Curr Opin Neurobiol. 2005;15(3):257–65. doi: 10.1016/j.conb.2005.05.010 15922581.
21. Burgess DL, Jones JM, Meisler MH, Noebels JL. Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse. Cell. 1997;88(3):385–92. doi: 10.1016/s0092-8674(00)81877-2 9039265.
22. Mark MD, Maejima T, Kuckelsberg D, Yoo JW, Hyde RA, Shah V, et al. Delayed postnatal loss of P/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations. J Neurosci. 2011;31(11):4311–26. doi: 10.1523/JNEUROSCI.5342-10.2011 21411672; PubMed Central PMCID: PMC3065835.
23. McEnery MW, Vance CL, Begg CM, Lee WL, Choi Y, Dubel SJ. Differential expression and association of calcium channel subunits in development and disease. J Bioenerg Biomembr. 1998;30(4):409–18. doi: 10.1023/a:1021997924473 9758336.
24. Ludwig A, Flockerzi V, Hofmann F. Regional expression and cellular localization of the alpha1 and beta subunit of high voltage-activated calcium channels in rat brain. J Neurosci. 1997;17(4):1339–49. doi: 10.1523/JNEUROSCI.17-04-01339.1997 9006977.
25. Castellano A, Wei X, Birnbaumer L, Perez-Reyes E. Cloning and expression of a neuronal calcium channel beta subunit. J Biol Chem. 1993;268(17):12359–66. 7685340.
26. Etemad S, Obermair GJ, Bindreither D, Benedetti A, Stanika R, Di Biase V, et al. Differential neuronal targeting of a new and two known calcium channel beta4 subunit splice variants correlates with their regulation of gene expression. J Neurosci. 2014;34(4):1446–61. doi: 10.1523/JNEUROSCI.3935-13.2014 24453333; PubMed Central PMCID: PMC3898300.
27. Obermair GJ, Schlick B, Di Biase V, Subramanyam P, Gebhart M, Baumgartner S, et al. Reciprocal interactions regulate targeting of calcium channel beta subunits and membrane expression of alpha1 subunits in cultured hippocampal neurons. J Biol Chem. 2010;285(8):5776–91. doi: 10.1074/jbc.M109.044271 19996312; PubMed Central PMCID: PMC2820804.
28. Subramanyam P, Obermair GJ, Baumgartner S, Gebhart M, Striessnig J, Kaufmann WA, et al. Activity and calcium regulate nuclear targeting of the calcium channel beta4b subunit in nerve and muscle cells. Channels (Austin). 2009;3(5):343–55. doi: 10.4161/chan.3.5.9696 19755859; PubMed Central PMCID: PMC2853709.
29. Tadmouri A, Kiyonaka S, Barbado M, Rousset M, Fablet K, Sawamura S, et al. Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy. EMBO J. 2012;31(18):3730–44. doi: 10.1038/emboj.2012.226 22892567; PubMed Central PMCID: PMC3442274.
30. Ronjat M, Kiyonaka S, Barbado M, De Waard M, Mori Y. Nuclear life of the voltage-gated Cacnb4 subunit and its role in gene transcription regulation. Channels (Austin). 2013;7(2):119–25. PubMed Central PMCID: PMC3667881. doi: 10.4161/chan.23895 23511121
31. Takahashi SX, Miriyala J, Colecraft HM. Membrane-associated guanylate kinase-like properties of beta-subunits required for modulation of voltage-dependent Ca2+ channels. Proc Natl Acad Sci U S A. 2004;101(18):7193–8. doi: 10.1073/pnas.0306665101 15100405; PubMed Central PMCID: PMC406488.
32. McGee AW, Nunziato DA, Maltez JM, Prehoda KE, Pitt GS, Bredt DS. Calcium channel function regulated by the SH3-GK module in beta subunits. Neuron. 2004;42(1):89–99. doi: 10.1016/s0896-6273(04)00149-7 15066267.
33. Hosford DA, Lin FH, Wang Y, Caddick SJ, Rees M, Parkinson NJ, et al. Studies of the lethargic (lh/lh) mouse model of absence seizures: regulatory mechanisms and identification of the lh gene. Adv Neurol. 1999;79:239–52. 10514818.
34. Benedetti B, Benedetti A, Flucher BE. Loss of the calcium channel beta4 subunit impairs parallel fibre volley and Purkinje cell firing in cerebellum of adult ataxic mice. Eur J Neurosci. 2016;43(11):1486–98. doi: 10.1111/ejn.13241 27003325; PubMed Central PMCID: PMC4949674.
35. Ohmori I, Ouchida M, Miki T, Mimaki N, Kiyonaka S, Nishiki T, et al. A CACNB4 mutation shows that altered Ca(v)2.1 function may be a genetic modifier of severe myoclonic epilepsy in infancy. Neurobiol Dis. 2008;32(3):349–54. doi: 10.1016/j.nbd.2008.07.017 18755274.
36. Harms FL, Kloth K, Bley A, Denecke J, Santer R, Lessel D, et al. Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder. Am J Hum Genet. 2018;103(4):579–91. doi: 10.1016/j.ajhg.2018.09.005 30290153; PubMed Central PMCID: PMC6174322.
37. Hempel M, Cremer K, Ockeloen CW, Lichtenbelt KD, Herkert JC, Denecke J, et al. De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment. Am J Hum Genet. 2015;97(3):493–500. doi: 10.1016/j.ajhg.2015.08.003 26340335; PubMed Central PMCID: PMC4564986.
38. Todorovic V, Finnegan E, Freyer L, Zilberberg L, Ota M, Rifkin DB. Long form of latent TGF-beta binding protein 1 (Ltbp1L) regulates cardiac valve development. Dev Dyn. 2011;240(1):176–87. doi: 10.1002/dvdy.22521 21181942; PubMed Central PMCID: PMC3012267.
39. Todorovic V, Frendewey D, Gutstein DE, Chen Y, Freyer L, Finnegan E, et al. Long form of latent TGF-beta binding protein 1 (Ltbp1L) is essential for cardiac outflow tract septation and remodeling. Development. 2007;134(20):3723–32. doi: 10.1242/dev.008599 17804598.
40. Gorski MM, Lecchi A, Femia EA, La Marca S, Cairo A, Pappalardo E, et al. Complications of whole-exome sequencing for causal gene discovery in primary platelet secretion defects. Haematologica. 2019;104(10):2084–90. doi: 10.3324/haematol.2018.204990 30819905.
41. Zanetti M, Braghetta P, Sabatelli P, Mura I, Doliana R, Colombatti A, et al. EMILIN-1 deficiency induces elastogenesis and vascular cell defects. Mol Cell Biol. 2004;24(2):638–50. doi: 10.1128/MCB.24.2.638-650.2004 14701737; PubMed Central PMCID: PMC343785.
42. Capuano A, Bucciotti F, Farwell KD, Tippin Davis B, Mroske C, Hulick PJ, et al. Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal-Dominant Hereditary Connective Tissue Disease. Hum Mutat. 2016;37(1):84–97. doi: 10.1002/humu.22920 26462740; PubMed Central PMCID: PMC4738430.
43. Ho RX, Meyer RD, Chandler KB, Ersoy E, Park M, Bondzie PA, et al. MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth. J Mol Cell Biol. 2018;10(3):195–204. doi: 10.1093/jmcb/mjy002 29329397; PubMed Central PMCID: PMC6025234.
44. Zhang H, Zhang Q, Gao G, Wang X, Wang T, Kong Z, et al. UBTOR/KIAA1024 regulates neurite outgrowth and neoplasia through mTOR signaling. PLoS Genet. 2018;14(8):e1007583. doi: 10.1371/journal.pgen.1007583 30080879; PubMed Central PMCID: PMC6095612.
45. Deciphering Developmental Disorders S. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542(7642):433–8. doi: 10.1038/nature21062 28135719; PubMed Central PMCID: PMC6016744.
46. Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg EJ, de Vries P, et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016;19(9):1194–6. doi: 10.1038/nn.4352 27479843.
47. Vissers LE, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17(1):9–18. doi: 10.1038/nrg3999 26503795.
48. Heyne HO, Singh T, Stamberger H, Abou Jamra R, Caglayan H, Craiu D, et al. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet. 2018;50(7):1048–53. doi: 10.1038/s41588-018-0143-7 29942082.
49. Reuter MS, Tawamie H, Buchert R, Hosny Gebril O, Froukh T, Thiel C, et al. Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders. JAMA Psychiatry. 2017;74(3):293–9. doi: 10.1001/jamapsychiatry.2016.3798 28097321.
50. Rifkin DB, Rifkin WJ, Zilberberg L. LTBPs in biology and medicine: LTBP diseases. Matrix Biol. 2018;71–72:90–9. doi: 10.1016/j.matbio.2017.11.014 29217273; PubMed Central PMCID: PMC5988920.
51. Colombatti A, Spessotto P, Doliana R, Mongiat M, Bressan GM, Esposito G. The EMILIN/Multimerin family. Front Immunol. 2011;2:93. doi: 10.3389/fimmu.2011.00093 22566882; PubMed Central PMCID: PMC3342094.
52. Latif Z, Chakchouk I, Schrauwen I, Lee K, Santos-Cortez RLP, Abbe I, et al. Confirmation of the Role of DHX38 in the Etiology of Early-Onset Retinitis Pigmentosa. Invest Ophthalmol Vis Sci. 2018;59(11):4552–7. doi: 10.1167/iovs.18-23849 30208423; PubMed Central PMCID: PMC6133250.
53. Ajmal M, Khan MI, Neveling K, Khan YM, Azam M, Waheed NK, et al. A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma. J Med Genet. 2014;51(7):444–8. doi: 10.1136/jmedgenet-2014-102316 24737827.
54. Rehman AU, Bird JE, Faridi R, Shahzad M, Shah S, Lee K, et al. Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness. Hum Mutat. 2016;37(10):991–1003. doi: 10.1002/humu.23042 27375115; PubMed Central PMCID: PMC5021573.
55. Wang A, Liang Y, Fridell RA, Probst FJ, Wilcox ER, Touchman JW, et al. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science. 1998;280(5368):1447–51. doi: 10.1126/science.280.5368.1447 9603736.
56. Hosford DA, Wang Y. Utility of the lethargic (lh/lh) mouse model of absence seizures in predicting the effects of lamotrigine, vigabatrin, tiagabine, gabapentin, and topiramate against human absence seizures. Epilepsia. 1997;38(4):408–14. doi: 10.1111/j.1528-1157.1997.tb01729.x 9118845.
57. McGee AW, Dakoji SR, Olsen O, Bredt DS, Lim WA, Prehoda KE. Structure of the SH3-guanylate kinase module from PSD-95 suggests a mechanism for regulated assembly of MAGUK scaffolding proteins. Mol Cell. 2001;8(6):1291–301. doi: 10.1016/s1097-2765(01)00411-7 11779504.
58. Shin H, Hsueh YP, Yang FC, Kim E, Sheng M. An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90. J Neurosci. 2000;20(10):3580–7. doi: 10.1523/JNEUROSCI.20-10-03580.2000 10804199.
59. McGee AW, Bredt DS. Identification of an intramolecular interaction between the SH3 and guanylate kinase domains of PSD-95. J Biol Chem. 1999;274(25):17431–6. doi: 10.1074/jbc.274.25.17431 10364172.
60. Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, et al. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015;10(2):148–61. doi: 10.1016/j.celrep.2014.12.015 25558065.
61. Anazi S, Maddirevula S, Salpietro V, Asi YT, Alsahli S, Alhashem A, et al. Expanding the genetic heterogeneity of intellectual disability. Hum Genet. 2017;136(11–12):1419–29. doi: 10.1007/s00439-017-1843-2 28940097.
62. Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009;84(4):524–33. doi: 10.1016/j.ajhg.2009.03.010 19344873.
63. Heyne HO, Artomov M, Battke F, Bianchini C, Smith DR, Liebmann N, et al. Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy. Genet Med. 2019;21(11):2496–2503. doi: 10.1038/s41436-019-0531-0 31056551.
64. Heyne HO, Singh T, Stamberger H, Abou Jamra R, Caglayan H, Craiu D, et al. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet. 2018;50(7):1048–53. doi: 10.1038/s41588-018-0143-7 29942082.
65. Karaca E, Harel T, Pehlivan D, Jhangiani SN, Gambin T, Coban Akdemir Z, et al. Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron. 2015;88(3):499–513. doi: 10.1016/j.neuron.2015.09.048 26539891; PubMed Central PMCID: PMC4824012.
66. Srivastava S, Cohen JS, Vernon H, Baranano K, McClellan R, Jamal L, et al. Clinical whole exome sequencing in child neurology practice. Ann Neurol. 2014;76(4):473–83. doi: 10.1002/ana.24251 25131622.
67. Study DDD. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542(7642):433–8. doi: 10.1038/nature21062 28135719; PubMed Central PMCID: PMC6016744.
68. Hu H, Kahrizi K, Musante L, Fattahi Z, Herwig R, Hosseini M, et al. Genetics of intellectual disability in consanguineous families. Mol Psychiatry. 2019;24(7):1027–39. doi: 10.1038/s41380-017-0012-2 29302074.
69. Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36(10):928–30. doi: 10.1002/humu.22844 26220891; PubMed Central PMCID: PMC4833888.
70. Wiel L, Baakman C, Gilissen D, Veltman JA, Vriend G, Gilissen C. MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. 2019;40(8):1030–1038. doi: 10.1002/humu.23798 31116477.
71. Etemad S, Campiglio M, Obermair GJ, Flucher BE. The juvenile myoclonic epilepsy mutant of the calcium channel beta(4) subunit displays normal nuclear targeting in nerve and muscle cells. Channels (Austin). 2014;8(4):334–43. doi: 10.4161/chan.29322 24875574; PubMed Central PMCID: PMC4203735.
72. Campiglio M, Coste de Bagneaux P, Ortner NJ, Tuluc P, Van Petegem F, Flucher BE. STAC proteins associate to the IQ domain of CaV1.2 and inhibit calcium-dependent inactivation. Proc Natl Acad Sci U S A. 2018;115(6):1376–81. doi: 10.1073/pnas.1715997115 29363593; PubMed Central PMCID: PMC5819422.
73. Tuluc P, Kern G, Obermair GJ, Flucher BE. Computer modeling of siRNA knockdown effects indicates an essential role of the Ca2+ channel alpha2delta-1 subunit in cardiac excitation-contraction coupling. Proc Natl Acad Sci U S A. 2007;104(26):11091–6. doi: 10.1073/pnas.0700577104 17563358; PubMed Central PMCID: PMC1904133.
74. Neuhuber B, Gerster U, Doring F, Glossmann H, Tanabe T, Flucher BE. Association of calcium channel alpha1S and beta1a subunits is required for the targeting of beta1a but not of alpha1S into skeletal muscle triads. Proc Natl Acad Sci U S A. 1998;95(9):5015–20. PubMed Central PMCID: PMC20205. doi: 10.1073/pnas.95.9.5015 9560220
75. Flucher BE, Andrews SB, Fleischer S, Marks AR, Caswell A, Powell JA. Triad formation: organization and function of the sarcoplasmic reticulum calcium release channel and triadin in normal and dysgenic muscle in vitro. J Cell Biol. 1993;123(5):1161–74. doi: 10.1083/jcb.123.5.1161 8245124; PubMed Central PMCID: PMC2119885.
76. Tanabe T, Beam KG, Powell JA, Numa S. Restoration of excitation-contraction coupling and slow calcium current in dysgenic muscle by dihydropyridine receptor complementary DNA. Nature. 1988;336(6195):134–9. doi: 10.1038/336134a0 2903448.
77. Campiglio M, Di Biase V, Tuluc P, Flucher BE. Stable incorporation versus dynamic exchange of beta subunits in a native Ca2+ channel complex. J Cell Sci. 2013;126(Pt 9):2092–101. doi: 10.1242/jcs.jcs124537 23447673; PubMed Central PMCID: PMC4148589.
78. Rima M, Daghsni M, De Waard S, Gaborit N, Fajloun Z, Ronjat M, et al. The beta4 subunit of the voltage-gated calcium channel (Cacnb4) regulates the rate of cell proliferation in Chinese Hamster Ovary cells. Int J Biochem Cell Biol. 2017;89:57–70. doi: 10.1016/j.biocel.2017.05.032 28587927.
79. Stark C, Breitkreutz BJ, Reguly T, Boucher L, Breitkreutz A, Tyers M. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 2006;34(Database issue):D535–9. doi: 10.1093/nar/gkj109 16381927; PubMed Central PMCID: PMC1347471.
80. Li J, Zhang W, Yang H, Howrigan DP, Wilkinson B, Souaiaia T, et al. Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders. Nat Neurosci. 2017;20(8):1150–61. doi: 10.1038/nn.4594 28671696; PubMed Central PMCID: PMC5645082.
81. Coba MP, Komiyama NH, Nithianantharajah J, Kopanitsa MV, Indersmitten T, Skene NG, et al. TNiK is required for postsynaptic and nuclear signaling pathways and cognitive function. J Neurosci. 2012;32(40):13987–99. doi: 10.1523/JNEUROSCI.2433-12.2012 23035106; PubMed Central PMCID: PMC3978779.
82. Shitashige M, Satow R, Jigami T, Aoki K, Honda K, Shibata T, et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 2010;70(12):5024–33. doi: 10.1158/0008-5472.CAN-10-0306 20530691
83. Mahmoudi T, Li VS, Ng SS, Taouatas N, Vries RG, Mohammed S, et al. The kinase TNIK is an essential activator of Wnt target genes. EMBO J. 2009;28(21):3329–40. PubMed Central PMCID: PMC2776109. doi: 10.1038/emboj.2009.285 19816403
84. Stephens GJ, Page KM, Bogdanov Y, Dolphin AC. The alpha1B Ca2+ channel amino terminus contributes determinants for beta subunit-mediated voltage-dependent inactivation properties. J Physiol. 2000;525 Pt 2:377–90. doi: 10.1111/j.1469-7793.2000.t01-1-00377.x 10835041; PubMed Central PMCID: PMC2269961.
85. Butcher AJ, Leroy J, Richards MW, Pratt WS, Dolphin AC. The importance of occupancy rather than affinity of CaV(beta) subunits for the calcium channel I-II linker in relation to calcium channel function. J Physiol. 2006;574(Pt 2):387–98. doi: 10.1113/jphysiol.2006.109744 16627564; PubMed Central PMCID: PMC1817768.
86. Gerster U, Neuhuber B, Groschner K, Striessnig J, Flucher BE. Current modulation and membrane targeting of the calcium channel alpha1C subunit are independent functions of the beta subunit. J Physiol. 1999;517 (Pt 2):353–68. doi: 10.1111/j.1469-7793.1999.0353t.x 10332087; PubMed Central PMCID: PMC2269342.
87. Neuhuber B, Gerster U, Mitterdorfer J, Glossmann H, Flucher BE. Differential effects of Ca2+ channel beta1a and beta2a subunits on complex formation with alpha1S and on current expression in tsA201 cells. J Biol Chem. 1998;273(15):9110–8. doi: 10.1074/jbc.273.15.9110 9535900.
88. Graves TD, Hanna MG. Channeling into the epilepsies. Epilepsy Curr. 2008;8(2):37–8. doi: 10.1111/j.1535-7511.2008.00229.x 18330464; PubMed Central PMCID: PMC2265808.
89. Dickie MM. Lethargic (lh). Mouse News Lett. 1964;30:31.
90. Sidman RL, Green MC, Appel SH. Catalog of the Neurological Mutants of the Mouse: Cambridge, Massachusetts: Harvard University Press; 1965. 34 p.
91. Hosford DA, Clark S, Cao Z, Wilson WA Jr., Lin FH, Morrisett RA, et al. The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice. Science. 1992;257(5068):398–401. doi: 10.1126/science.1321503 1321503.
92. Reinson K, Oiglane-Shlik E, Talvik I, Vaher U, Ounapuu A, Ennok M, et al. Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy. Am J Med Genet A. 2016;170(8):2173–6. doi: 10.1002/ajmg.a.37678 27250579.
93. Rima M, Daghsni M, Lopez A, Fajloun Z, Lefrancois L, Dunach M, et al. Down-regulation of the Wnt/beta-catenin signaling pathway by Cacnb4. Mol Biol Cell. 2017;28(25):3699–708. doi: 10.1091/mbc.E17-01-0076 29021340; PubMed Central PMCID: PMC5706996.
94. Chen X, Shibata AC, Hendi A, Kurashina M, Fortes E, Weilinger NL, et al. Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in C. elegans. Elife. 2018;7. doi: 10.7554/eLife.38801 30063210; PubMed Central PMCID: PMC6067881.
95. Anazi S, Shamseldin HE, AlNaqeb D, Abouelhoda M, Monies D, Salih MA, et al. A null mutation in TNIK defines a novel locus for intellectual disability. Hum Genet. 2016;135(7):773–8. doi: 10.1007/s00439-016-1671-9 27106596.
96. Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5. doi: 10.1038/ng.2892 24487276; PubMed Central PMCID: PMC3992975.
97. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet. 2016;99(4):877–85. doi: 10.1016/j.ajhg.2016.08.016 27666373.
98. Jagadeesh KA, Wenger AM, Berger MJ, Guturu H, Stenson PD, Cooper DN, et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet. 2016;48(12):1581–6. doi: 10.1038/ng.3703 27776117.
99. Grabner M, Dirksen RT, Beam KG. Tagging with green fluorescent protein reveals a distinct subcellular distribution of L-type and non-L-type Ca2+ channels expressed in dysgenic myotubes. Proc Natl Acad Sci U S A. 1998;95(4):1903–8. doi: 10.1073/pnas.95.4.1903 9465115; PubMed Central PMCID: PMC19211.
100. Powell JA, Petherbridge L, Flucher BE. Formation of triads without the dihydropyridine receptor alpha subunits in cell lines from dysgenic skeletal muscle. J Cell Biol. 1996;134(2):375–87. doi: 10.1083/jcb.134.2.375 8707823; PubMed Central PMCID: PMC2120881.
101. Folci A, Steinberger A, Lee B, Stanika R, Scheruebel S, Campiglio M, et al. Molecular mimicking of C-terminal phosphorylation tunes the surface dynamics of CaV1.2 calcium channels in hippocampal neurons. J Biol Chem. 2018;293(3):1040–53. doi: 10.1074/jbc.M117.799585 29180451; PubMed Central PMCID: PMC5777246.
102. Kaech S, Banker G. Culturing hippocampal neurons. Nat Protoc. 2006;1(5):2406–15. doi: 10.1038/nprot.2006.356 17406484.
103. Obermair GJ, Szabo Z, Bourinet E, Flucher BE. Differential targeting of the L-type Ca2+ channel alpha 1C (CaV1.2) to synaptic and extrasynaptic compartments in hippocampal neurons. Eur J Neurosci. 2004;19(8):2109–22. doi: 10.1111/j.0953-816X.2004.03272.x 15090038.
104. Stanika R, Campiglio M, Pinggera A, Lee A, Striessnig J, Flucher BE, et al. Splice variants of the CaV1.3 L-type calcium channel regulate dendritic spine morphology. Sci Rep. 2016;6:34528. doi: 10.1038/srep34528 27708393; PubMed Central PMCID: PMC5052568.
105. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–82. doi: 10.1038/nmeth.2019 22743772; PubMed Central PMCID: PMC3855844.
106. Hitzl M, Striessnig J, Neuhuber B, Flucher BE. A mutation in the beta interaction domain of the Ca(2+) channel alpha(1C) subunit reduces the affinity of the (+)-[(3)H]isradipine binding site. FEBS Lett. 2002;524(1–3):188–92. doi: 10.1016/s0014-5793(02)03054-5 12135765.
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