Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder

Journal of Clinical Investigation

Volumn 127, Issue 3, 2017, Pages 1005-1018

  Lipstein, Noa ^a   Verhoeven Duif, Nanda M ^b,c   Michelassi, Francesco E ^d   Calloway, Nathaniel ^d   Van Hasselt, Peter M ^e   Pienkowska, Katarzyna ^a   Van Haaften, Gijs ^b,c   Van Haelst, Mieke M ^c   Van Empelen, Ron ^c   Cuppen, Inge ^e   Van Teeseling, Heleen C ^f   Evelein, Annemieke M V ^c   Vorstman, Jacob A ^c   Thoms, Sven ^g   Jahn, Olaf ^a   Duran, Karen J ^b,c   Monroe, Glen R ^b,c   Ryan, Timothy A ^d   Taschenberger, Holger ^a   Dittman, Jeremy S ^d   Rhee, Jeong Seop ^a   Visser, Gepke ^e   Jans, Judith J ^c   Brose, Nils ^a   more..

^a MAX PLANCK INSTITUTE OF EXPERIMENTAL MEDICINE   (Germany)

^b Center for Molecular Medicine   (Netherlands)

^c UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^d WEILL CORNELL MEDICAL COLLEGE   (United States)

^e UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^f Sector of Neuropsychology ^*  (Netherlands)

^g UNIVERSITY OF GÖTTINGEN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

METHYLPHENIDATE; PROTEIN; PROTEIN VARIANT; UNC13A PROTEIN; UNCLASSIFIED DRUG; CAENORHABDITIS ELEGANS PROTEIN; NERVE PROTEIN; UNC13A PROTEIN, MOUSE; UNC13B PROTEIN, HUMAN;

ANIMAL BEHAVIOR; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; ATTENTION DEFICIT DISORDER; AUTISM; BAYLEY SCALES OF INFANT DEVELOPMENT; BIOINFORMATICS; CAENORHABDITIS ELEGANS; CASE REPORT; CHILD; COMPULSION; DEVELOPMENTAL DISORDER; DNA ISOLATION; DRUG DOSE INCREASE; DYSKINESIA; ELECTROPHYSIOLOGY; GENE MUTATION; HUMAN; IMPULSIVENESS; MALE; MORNING DOSAGE; MOUSE; NERVE CELL CULTURE; NERVE CELL PLASTICITY; NEUROTRANSMISSION; NONHUMAN; PRESCHOOL CHILD; PRESYNAPTIC POTENTIAL; SYNAPSE VESICLE; SYNAPTIC TRANSMISSION; WHOLE EXOME SEQUENCING; AMINO ACID SUBSTITUTION; ANIMAL; CELL LINE; FEMALE; GENETICS; INFANT; METABOLISM; MISSENSE MUTATION; MOTOR DYSFUNCTION; NERVE CELL;

AMINO ACID SUBSTITUTION; ANIMALS; CAENORHABDITIS ELEGANS; CAENORHABDITIS ELEGANS PROTEINS; CELL LINE; FEMALE; HUMANS; INFANT; MALE; MOTOR DISORDERS; MUTATION, MISSENSE; NERVE TISSUE PROTEINS; NEURONAL PLASTICITY; NEURONS; SYNAPTIC TRANSMISSION; SYNAPTIC VESICLES;

EID: 85015969576     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI90259     Document Type: Article

References (91)

1. Blier P, El Mansari M. Serotonin and beyond: therapeutics for major depression. Philos Trans R Soc Lond B Biol Sci. 2013;368(1615):20120536.
2. Boyd KN, Mailman RB. Dopamine receptor signaling and current and future antipsychotic drugs. Handb Exp Pharmacol. 2012;(212):53-86.
3. Musazzi L, Treccani G, Mallei A, Popoli M. The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors. Biol Psychiatry. 2013;73(12):1180-1188.
4. Agid Y, et al. How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov. 2007;6(3):189-201.
5. Südhof TC. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron. 2013;80(3):675-690.
6. Wojcik SM, Brose N. Regulation of membrane fusion in synaptic excitation-secretion coupling: speed and accuracy matter. Neuron. 2007;55(1):11-24.
7. Giovedí S, Corradi A, Fassio A, Benfenati F. Involvement of synaptic genes in the pathogenesis of autism spectrum disorders: the case of synapsins. Front Pediatr. 2014;2:94.
8. Hamdan FF, et al. De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann Neurol. 2009;65(6):748-753.
9. Deprez L, et al. Clinical spectrum of earlyonset epileptic encephalopathies associated with STXBP1 mutations. Neurology. 2010;75(13):1159-1165.
10. Carvill GL, et al. GABRA1 and STXBP1: novel genetic causes of Dravet syndrome. Neurology. 2014;82(14):1245-1253.
11. Otsuka M, et al. STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome-result of Japanese cohort study. Epilepsia. 2010;51(12):2449-2452.
12. Saitsu H, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40(6):782-788.
13. Nosková L, et al. Mutations in DNAJC5, encoding cysteine-string protein, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am J Hum Genet. 2011;89(2):241-252.
14. Ozansoy M, Baak AN. The central theme of Parkinson's disease: synuclein. Mol Neurobiol. 2013;47(2):460-465.
15. Rizo J, Südhof TC. The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices-guilty as charged? Annu Rev Cell Dev Biol. 2012;28:279-308.
16. Lee HY, et al. The gene for paroxysmal nonkinesigenic dyskinesia encodes an enzyme in a stress response pathway. Hum Mol Genet. 2004;13(24):3161-3170.
17. Lee HY, et al. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep. 2012;1(1):2-12.
18. Shen Y, et al. Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis. Proc Natl Acad Sci U S A. 2015;112(10):2935-2941.
19. Baker K, et al. Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling. J Clin Invest. 2015;125(4):1670-1678.
20. Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381(9875):1371-1379.
21. De Rubeis S, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209-215.
22. Fromer M, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506(7487):179-184.
23. Gai X, et al. Rare structural variation of synapse and neurotransmission genes in autism. Mol Psychiatry. 2012;17(4):402-411.
24. Purcell SM, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506(7487):185-190.
25. Augustin I, Rosenmund C, Südhof TC, Brose N. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature. 1999;400(6743):457-461.
26. Varoqueaux F, et al. Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. Proc Natl Acad Sci U S A. 2002;99(13):9037-9042.
27. Ashery U, et al. Munc13-1 acts as a priming factor for large dense-core vesicles in bovine chromaffin cells. EMBO J. 2000;19(14):3586-3596.
28. Augustin I, et al. The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice. J Neurosci. 2001;21(1):10-17.
29. Rosenmund C, Sigler A, Augustin I, Reim K, Brose N, Rhee JS. Differential control of vesicle priming and short-term plasticity by Munc13 isoforms. Neuron. 2002;33(3):411-424.
30. Richmond JE, Weimer RM, Jorgensen EM. An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature. 2001;412(6844):338-341.
31. Yang X, et al. Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming. Nat Struct Mol Biol. 2015;22(7):547-554.
32. Basu J, Betz A, Brose N, Rosenmund C. Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion. J Neurosci. 2007;27(5):1200-1210.
33. Junge HJ, et al. Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity. Cell. 2004;118(3):389-401.
34. Lipstein N, et al. Dynamic control of synaptic vesicle replenishment and short-term plasticity by Ca(2+)-calmodulin-Munc13-1 signaling. Neuron. 2013;79(1):82-96.
35. Lipstein N, et al. Nonconserved Ca(2+)/calmodulin binding sites in Munc13s differentially control synaptic short-term plasticity. Mol Cell Biol. 2012;32(22):4628-4641.
36. Rhee JS, et al. Beta phorbol ester-and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell. 2002;108(1):121-133.
37. Shin OH, et al. Munc13 C2B domain is an activitydependent Ca2+ regulator of synaptic exocytosis. Nat Struct Mol Biol. 2010;17(3):280-288.
38. Abbott LF, Varela JA, Sen K, Nelson SB. Synaptic depression and cortical gain control. Science. 1997;275(5297):220-224.
39. Chung S, Li X, Nelson SB. Short-term depression at thalamocortical synapses contributes to rapid adaptation of cortical sensory responses in vivo. Neuron. 2002;34(3):437-446.
40. Nadim F, Manor Y. The role of short-term synaptic dynamics in motor control. Curr Opin Neurobiol. 2000;10(6):683-690.
41. Nadim F, Manor Y, Kopell N, Marder E. Synaptic depression creates a switch that controls the frequency of an oscillatory circuit. Proc Natl Acad Sci U S A. 1999;96(14):8206-8211.
42. Mongillo G, Barak O, Tsodyks M. Synaptic theory of working memory. Science. 2008;319(5869):1543-1546.
43. Traub RD, et al. Transient depression of excitatory synapses on interneurons contributes to epileptiform bursts during gamma oscillations in the mouse hippocampal slice. J Neurophysiol. 2005;94(2):1225-1235.
44. Augustin I, Betz A, Herrmann C, Jo T, Brose N. Differential expression of two novel Munc13 proteins in rat brain. Biochem J. 1999;337(pt 3):363-371.
45. Varoqueaux F, Sons MS, Plomp JJ, Brose N. Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse. Mol Cell Biol. 2005;25(14):5973-5984.
46. Engel AG, Selcen D, Shen XM, Milone M, Harper CM. Loss of MUNC13-1 function causes microcephaly, cortical hyperexcitability, and fatal myasthenia. Neurol Genet. 2016;2(5):e105.
47. Bayley N. Manual for the Bayley Scales of Infant Development. 2nd ed. San Antonio, Texas, USA: The Psychological Corp.; 1993.
48. Meulen BFvd, Ruiter SAJ, Lutje Spelberg HC, Smrkovský M. Bayley Scales of Infant Development-II-Dutch Adaptation. Amsterdam, Netherlands: Harcourt Test Publishers; 2004.
49. Werpup-Stüwe L, Petermann F, Daseking M. [The impact of visual perceptual abilities on the performance on the Wechsler nonverbal scale of ability (WNV)]. Gesundheitswesen. 2015;77(10):799-804.
50. Lek M, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285-291.
51. Genome of the Netherlands Consortium. Wholegenome sequence variation, population structure and demographic history of the Dutch population. Nat Genet. 2014;46(8):818-825.
52. Adzhubei IA, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-249.
53. Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31(13):3812-3814.
54. Basu J, et al. A minimal domain responsible for Munc13 activity. Nat Struct Mol Biol. 2005;12(11):1017-1018.
55. Burgalossi A, et al. Analysis of neurotransmitter release mechanisms by photolysis of caged Ca2+ in an autaptic neuron culture system. Nat Protoc. 2012;7(7):1351-1365.
56. Jockusch WJ, et al. CAPS-1 and CAPS-2 are essential synaptic vesicle priming proteins. Cell. 2007;131(4):796-808.
57. Rhee JS, et al. Augmenting neurotransmitter release by enhancing the apparent Ca2+ affinity of synaptotagmin 1. Proc Natl Acad Sci U S A. 2005;102(51):18664-18669.
58. Xue M, et al. Distinct domains of complexin I differentially regulate neurotransmitter release. Nat Struct Mol Biol. 2007;14(10):949-958.
59. Imig C, et al. The morphological and molecular nature of synaptic vesicle priming at presynaptic active zones. Neuron. 2014;84(2):416-431.
60. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77(1):71-94.
61. Mahoney TR, Luo S, Nonet ML. Analysis of synaptic transmission in Caenorhabditis elegans using an aldicarb-sensitivity assay. Nat Protoc. 2006;1(4):1772-1777.
62. Rosenmund C, Stevens CF. Definition of the readily releasable pool of vesicles at hippocampal synapses. Neuron. 1996;16(6):1197-1207.
63. Betz A, et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron. 1998;21(1):123-136.
64. Wierda KD, Toonen RF, de Wit H, Brussaard AB, Verhage M. Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity. Neuron. 2007;54(2):275-290.
65. Lou X, Korogod N, Brose N, Schneggenburger R. Phorbol esters modulate spontaneous and Ca2+-evoked transmitter release via acting on both Munc13 and protein kinase C. J Neurosci. 2008;28(33):8257-8267.
66. de Jong AP, et al. Phosphorylation of synaptotagmin-1 controls a post-priming step in PKCdependent presynaptic plasticity. Proc Natl Acad Sci U S A. 2016;113(18):5095-5100.
67. Wesseling JF, Lo DC. Limit on the role of activity in controlling the release-ready supply of synaptic vesicles. J Neurosci. 2002;22(22):9708-9720.
68. Betz A, et al. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron. 2001;30(1):183-196.
69. Stevens DR, et al. Identification of the minimal protein domain required for priming activity of Munc13-1. Curr Biol. 2005;15(24):2243-2248.
70. Calloway N, Gouzer G, Xue M, Ryan TA. The active-zone protein Munc13 controls the usedependence of presynaptic voltage-gated calcium channels. Elife. 2015;4:e07728.
71. Egawa J, et al. Rare UNC13B variations and risk of schizophrenia: Whole-exome sequencing in a multiplex family and follow-up resequencing and a case-control study. Am J Med Genet B Neuropsychiatr Genet. 2016;171(6):797-805.
72. Pizoli CE, Jinnah HA, Billingsley ML, Hess EJ. Abnormal cerebellar signaling induces dystonia in mice. J Neurosci. 2002;22(17):7825-7833.
73. Lee HY, et al. Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia. J Clin Invest. 2012;122(2):507-518.
74. Schoch S, et al. RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zone. Nature. 2002;415(6869):321-326.
75. Lu J, et al. Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLoS Biol. 2006;4(7):e192.
76. Stelzl U, et al. A human protein-protein interaction network: a resource for annotating the proteome. Cell. 2005;122(6):957-968.
77. Valente P, et al. PRRT2 is a key component of the Ca(2+)-dependent neurotransmitter release machinery. Cell Rep. 2016;15(1):117-131.
78. Scheffer IE, et al. PRRT2 phenotypic spectrum includes sporadic and fever-related infantile seizures. Neurology. 2012;79(21):2104-2108.
79. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text revision. Washington, DC, USA: American Psychiatric Press; 2000.
80. Annelies de Bildt MdJ, Greaves-Lord K. ADOS-2 Autisme Diagnostisch Observatieschema Hogrefe; 2013.
81. Maretha de Jonge AdB, Ann Le Couteur, Catherine Lord, Michael Rutter. ADi-R Autisme Diagnostisch Interview-Revised. Hogrefe; 2012.
82. Harakalova M, et al. Dominant missense mutations in ABCC9 cause Cantú syndrome. Nat Genet. 2012;44(7):793-796.
83. Hsia HE, et al. Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth. Proc Natl Acad Sci U S A. 2014;111(36):13205-13210.
84. Naldini L, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272(5259):263-267.
85. Bekkers JM, Stevens CF. Excitatory and inhibitory autaptic currents in isolated hippocampal neurons maintained in cell culture. Proc Natl Acad Sci U S A. 1991;88(17):7834-7838.
86. Nair R, et al. Neurobeachin regulates neurotransmitter receptor trafficking to synapses. J Cell Biol. 2013;200(1):61-80.
87. Dittman JS, Kaplan JM. Behavioral impact of neurotransmitter-activated G-protein-coupled receptors: muscarinic and GABAB receptors regulate Caenorhabditis elegans locomotion. J Neurosci. 2008;28(28):7104-7112.
88. Koch H, Hofmann K, Brose N. Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform. Biochem J. 2000;349(pt 1):247-253.
89. Liu X, et al. Functional synergy between the Munc13 C-terminal C1 and C2 domains. Elife. 2016;5:e13696.
90. Betz A, Okamoto M, Benseler F, Brose N. Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. J Biol Chem. 1997;272(4):2520-2526.
91. Brose N, Hofmann K, Hata Y, Südhof TC. Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem. 1995;270(42):25273-25280.