Table of Contents    
Editorial
 
Are all types of migraine channelopathies?
Wenjing Tang1, Shengyuan Yu2
1Postdoctor of the Department of Neurology, Chinese PLA General Hospital, Beijing, China.
2Professor and Director of the Department of Neurology, Chinese PLA General Hospital, Beijing, China.

Article ID: 100006N06WT2015
doi:10.5348/N06-2015-6-ED-5

Address correspondence to:
Shengyuan Yu
Fuxing Road 28, Haidian District
Beijing
China -100853
Phone: 86-10-66939963
Fax: 86-10-88626299

Access full text article on other devices

  Access PDF of article on other devices

[HTML Abstract]   [PDF Full Text] [Print This Article]
[Similar article in Pumed] [Similar article in Google Scholar]

How to cite this article
Tang W, Yu S. Are all types of migraine channelopathies? Edorium J Neurol 2015;2:18–23.

Migraine is a typical episodic brain disorder. Based on migraine attacks with or without transient aura symptoms, migraine can be divided into migraine with aura (MA, including visual, sensory, motor, or speech difficulties) and migraine without aura (MO). Cortical spreading depression (CSD) is believed as the pathophysiological mechanism of aura. Familial hemiplegic migraine (FHM) is an autosomal dominant migraine with hemiplegic aura, which is extensively researched as a migraine model for pathophysiology because of the definite mutations of three disease-causing genes coding ion channels. Numerous studies on CSD and FHM tried to elucidate the role of ion channels in the migraine development. Studies on ion channel antagonists also showed efficiency in migraine prophylactic treatment. All above bring a false appearance that migraine is a channelopathy. However, with the discovery of PRRT2 gene related brain disorders, it is challenging whether migraine, even FHM, is a channelopathy. Over 5000 SNPs of 155 ion channel coding genes were all denied the connection between themselves and migraine susceptibility by a candidate gene linkage study. And genome-wide association studies not only denied the connection between common migraine and the three FHM causing genes, but also found 12 non-ion channel coding genes highly related to common migraine. More and more contrary evidences indicate that migraine is a kind of ion channel related disorder, which needs further studies on multiple levels from one single gene function to several genes and their encoding ion channels interactions.

Migraine is a primary brain disorder, causing episodic headache attacks with photophobia, phonophobia, nausea and vomiting [1]. It has been confirmed that migraine is highly impacted by genetic factors [2], and most of basic understanding of neurobiological mechanisms are contributed to genetic studies on aura and pain pathways in migraine [3].

Channelopathy has three features:

  1. symptoms often present as paroxysmal attacks with normal function interictally;
  2. most channelopathies are inherited as autosomal dominant traits;
  3. most channelopathies cause single-organ involvement [4].

Familial hemiplegic migraine (FHM) is characterized by migraine attacks, which is with transient, unilateral motor weakness as its episodic aura. FHM is an autosomal dominant migraine, three encoding protein genes have been identified: CACNA1A encodes a1 subunit of calcium channel Cav2.1 [5], ATP1A2 encodes a2 subunit of Na+/K+-ATPase pump [6], and SCN1A encodes a subunit of sodium channel Nav1.1 [7]. All these proteins are specially expressed on nervous system, and all the mutations mainly cause brain dysfunction [5] [6] [7]. Series studies on FHM indicated that mutations on Cav2.1 and ATP1A2 increased the concentration of glutamate in synapses and disturbed the excitatory and inhibitory balance, which induced the brain dysfunction [8]. Although the same result has not yet been concluded firmly enough from the functional studies on sodium channels (Nav1.1) owe to the more perplexed expression and structure of Nav1.1 and its encoding gene SCN1A [9] [10] [11], it firmly concluded that all the mutations of the three genes cause brain dysfunction [5] [6] [7]. All above indicate that FHM is a definitely channelopathy. Are other types of migraine channelopathies?

It is believed that cortical spreading depression (CSD) contributes to aura [12] [13] [14], which is a slowly propagating wave, causing depolarization of neural cells and silencing brain electrical activity for several minutes [12] [13] [14]. Studies focusing on CSD described a scenario of collapsing of ion homeostasis, which included a rapid outward current of K+, a rapid inward current of Na+, Ca2+ and Cl-, and a transient inward current of H+ [13] [15] [16]. This scenario causes Ca2+ intracellular increasing while K+ and glutamate releasing to the interstitium, which changes the excitability of local brain cells then turns on a positive-feedback cycle and finally induces brain dysfunction resulting in migraine [8] [12][17]. Multiple ion channels involve in different stages of the initiation and propagation of CSD, which implies that CSD is a presentation of channelopathies or ion channel related disorders and migraine with aura may be channelopathic disorder.

Many other studies focused on the activation and sensitization of trigeminovascular system (TGVS), which mainly involved in the releasing vasoactive proinflammatory factors from trigeminal ganglion cells, meningeal neurogenic inflammation surrounding the perivascular afferents, and the formation of a positive feedback triggering the next endogenous neurogenic inflammatory process [18] [19] [20] [21]. Most receptors of proinflammatory factors are ion channels, including voltage-gated ion channels and ligand-gated ion channels: sodium channels (Nav1.7, Nav1.8, Nav1.9) [22], potassium channels (K2P, KV1, etc.) [23] [24] [25], ATP receptors (P2X) [26] [27], acid-sensing ion channels (ASICs) [28] [29] , transient receptor potential (TRP) ion channel family (TRPV1, TRPA1, TRPM8, etc.) [30] [31] , etc. All of them can be found around the sensitized trigeminal nuclei, trigeminal ganglia and related blood vessels [18] [32][33][34]. However, these ion channels can also be found in dorsal root ganglia, dorsal horn of the spinal cord and different levels along the pain pathway in neuropathic pain [35] [36], which means that these ion channels are not specific to the migraine pathophysiology and it seems that these ion channels need exogenic triggers to be activated, but triggers of migraine originate from nervous system itself. Thus, ion channels involved in the activation and sensitization of TGVS just proved that migraine is an ion-channel related disorder.

Another indirect evidence to prove that migraine is highly associated with ion channel is that some effective prophylactic drugs for migraine such as amitriptyline, valproate and topiramate could inactivate sodium channels and other ion channels [22] [37] [38].

All above suggest that ion channel is an essential part of migraine pathophysiology, but not all types of migraine are channelopathies.

First, not all genes linked to monogenic migraine syndromes encode ion channels. One third of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients suffer from migraine with aura in the third decade of life [39]. Mutations in NOTCH3 have been identified as the responsible cause, which encodes Notch3 on cell membrane and interacts with its ligands, provoking intracellular GPCR and ERK signaling pathways, mediating the neurogenesis and angiogenesis [40] [41][42]. So far, it remains unknown how the NOTCH3 mutations in CADASIL triggers aura and headache, and whether these mutations lead to CSD and ionic chaos [43]. The similar condition has also been found in RVCL (retinal vasculopathy with cerebral leukodystrophy) with TREX1 mutations [44], and FASPS (familial advanced sleep phase syndrome) with CSNK1D mutations [45]. TREX1 is the coding gene of a nuclear protein, three prime repair exonuclease 1 [44]; while CSNK1D is a member of the casein kinase I gene family and its corresponding protein may regulate DNA replication and repairing [46]. Both of them seem irrelevant to ion channels. The mutations of PRRT2 cause a series brain disorders which had been usually regarded as channelopathies: hemiplegic migraine, infantile convulsions, paroxysmal dyskinesia [47]. However, PRRT2 encodes a transmembrane protein with a proline-rich domain in N-terminal half and is predominantly expressed in central nervous system during fetal and postnatal stages [47] [48]. Yeast 2-hybrid experiment elucidates that PRRT2 modulates the neurotransmitters releasing indirectly by interacting with synaptosomal-associated protein 25 kDA (SNAP25), which means PRRT2 mutations can interfere the excitatory - inhibitory homeostasis indirectly though it is not an ion channel protein [49]. Considered as the fourth FHM gene by more neurologists, the emergence of PRRT2 implies that migraine is far more than a channelopathy.

Second, both candidate gene association study and genome-wide associated study (GWAS) failed to confirm the involvement of ion channel genes in common migraineurs. Nyholt et al. screened 5257 SNPs covering 155 ion channel genes in over 3 thousand migraineurs, but none of them has a positive association [50]. Bouje et al. from the international headache genetics consortium re-evaluated genes from candidate gene association studies in migraine systematically using a large GWA data set. And the result was also negative, even the three well-known FHM genes all showed negative evidence for the involvement in common polygenic migraine [51]. A possible theory to explain the results above is that common migraine has multiple susceptibility genes which modulate ion and neurotransmitter homeostasis in a more subtle and multiplex manner, compared with monogenic migraine [3].

Third, three large GWASs and a subsequent meta-analysis identified 13 susceptibility genes underlying common migraine based on large population [3]. Except TRPM8, other 12 genes all encode non-ion channel proteins. Screened those 12 genes on NCBI Gene database, we found that most of them are highly-related to cell migration and differentiation. MEF2D, ASTN2 have been found in nervous system exerting a role in neural cell differentiation and development [52] [53] ; PHACTR1 exerts a regulating function of angiogenesis and vascular endothelial cells [54]; PRDM16 and FHL5 are transcription factors of cellular differentiation or maturation, while TGFBR2 belongs to the TGFR superfamily which modulates the transcription of proliferation relevant proteins, especially in the vascular endothelial cell proliferation process [55] [56][57]; TSPAN2 expresses on cellular membrane, while MMP16 in extracellular matrix, both exert a broad function in cell development, activation, modeling and motion [58] [59]. So far, a few experiments have showed that AJAP1 is a tumor suppressor while others indicated that MTDH is an oncogenesis factor, especially for astrocytoma [60] [61]. And LRP1 is the only protein to hinder cell apoptosis and acts as a scavenger of toxic protein deposit [62] [63]. Tolner et al. speculated the possible roles of these genes in the migraine pathophysiology [3], but the results of GWASs still need to be confirmed in functional and ethnological studies [3]. The results from GWASs further imply that as a complicated neurological condition, migraine involving in multifactorial mechanisms disturbing the brain homeostasis from single causal gene to multiple genes interact with each other [64], from molecules to the whole nervous system, from genotype to phenotype, not only limited in ion channels.

Migraine pathophysiology has been studied over 30 decades, but the mist on it is still uncovered. To the channelopathies, migraine may be one part of its wide range of clinical spectrum; to the genetic vasculopathies, migraine may be one symptom of its wide range of clinical manifestations; to the migraine itself, it is an unstable condition of different levels in nervous system including brain tissue, trigeminovascular system and nociceptors on meninges, and each level may have several factors finally make headache happen. As a multifactorial disorder, ion channel is a pivotal part involving in migraine development, the relationship between ion channel and migraine needs to be studied further.

Keywords: Channelopathy, Ion channel, Ion-channel related disorder, Migraine

Acknowledgements

Thanks for supporting by the National Natural Science Foundation of China (Grants81171058 and 81471147) and Clinical Support Fund of Chinese PLAGeneral Hospital (Grant 2014FC-CXYY-1006).


References
  1. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013 Jul;33(9):629–808.   [CrossRef]   [Pubmed]    Back to citation no. 1
  2. Russell MB, Ulrich V, Gervil M, Olesen J. Migraine without aura and migraine with aura are distinct disorders. A population-based twin survey. Headache 2002 May;42(5):332–6.   [CrossRef]   [Pubmed]    Back to citation no. 2
  3. Tolner EA, Houben T, Terwindt GM, de Vries B, Ferrari MD, van den Maagdenberg AM. From migraine genes to mechanisms. Pain 2015 Apr;156 Suppl 1:S64–74.   [CrossRef]   [Pubmed]    Back to citation no. 3
  4. Cannon SC. Physiologic principles underlying ion channelopathies. Neurotherapeutics 2007 Apr;4(2):174–83.   [CrossRef]   [Pubmed]    Back to citation no. 4
  5. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996 Nov 1;87(3):543–52.   [CrossRef]   [Pubmed]    Back to citation no. 5
  6. De Fusco M, Marconi R, Silvestri L, et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003 Feb;33(2):192–6.   [Pubmed]    Back to citation no. 6
  7. Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005 Jul 30-Aug 5;366(9483):371–7.   [CrossRef]   [Pubmed]    Back to citation no. 7
  8. Vecchia D, Pietrobon D. Migraine: a disorder of brain excitatory-inhibitory balance? Trends Neurosci 2012 Aug;35(8):507–20.   [CrossRef]   [Pubmed]    Back to citation no. 8
  9. Kahlig KM, Rhodes TH, Pusch M, et al. Divergent sodium channel defects in familial hemiplegic migraine. Proc Natl Acad Sci U S A 2008 Jul 15;105(28):9799–804.   [CrossRef]   [Pubmed]    Back to citation no. 9
  10. Cestèle S, Scalmani P, Rusconi R, Terragni B, Franceschetti S, Mantegazza M. Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the Nav1.1 (SCN1A) Na+ channel. J Neurosci 2008 Jul 16;28(29):7273–83.   [CrossRef]   [Pubmed]    Back to citation no. 10
  11. Cestèle S, Schiavon E, Rusconi R, Franceschetti S, Mantegazza M. Nonfunctional NaV1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects. Proc Natl Acad Sci U S A 2013 Oct 22;110(43):17546–51.   [CrossRef]   [Pubmed]    Back to citation no. 11
  12. Pietrobon D, Moskowitz MA. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Rev Neurosci 2014 Jun;15(6):379–93.   [CrossRef]   [Pubmed]    Back to citation no. 12
  13. Somjen GG. Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 2001 Jul;81(3):1065–96.   [Pubmed]    Back to citation no. 13
  14. Lauritzen M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 1994 Feb;117 ( Pt 1):199–210.   [Pubmed]    Back to citation no. 14
  15. Peters O, Schipke CG, Hashimoto Y, Kettenmann H. Different mechanisms promote astrocyte Ca2+ waves and spreading depression in the mouse neocortex. J Neurosci 2003 Oct 29;23(30):9888–96.   [Pubmed]    Back to citation no. 15
  16. Aiba I, Shuttleworth CW. Sustained NMDA receptor activation by spreading depolarizations can initiate excitotoxic injury in metabolically compromised neurons. J Physiol 2012 Nov 15;590(Pt 22):5877–93.   [CrossRef]   [Pubmed]    Back to citation no. 16
  17. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol 2013;75:365–91.   [CrossRef]   [Pubmed]    Back to citation no. 17
  18. Strassman AM, Raymond SA, Burstein R. Sensitization of meningeal sensory neurons and the origin of headaches. Nature 1996 Dec 12;384(6609):560–4.   [CrossRef]   [Pubmed]    Back to citation no. 18
  19. Waeber C, Moskowitz MA. Migraine as an inflammatory disorder. Neurology 2005 May 24;64(10 Suppl 2):S9–15.   [CrossRef]   [Pubmed]    Back to citation no. 19
  20. Levy D. Migraine pain, meningeal inflammation, and mast cells. Curr Pain Headache Rep 2009 Jun;13(3):237–40.   [CrossRef]   [Pubmed]    Back to citation no. 20
  21. Levy D. Endogenous mechanisms underlying the activation and sensitization of meningeal nociceptors: the role of immuno-vascular interactions and cortical spreading depression. Curr Pain Headache Rep 2012 Jun;16(3):270–7.   [CrossRef]   [Pubmed]    Back to citation no. 21
  22. Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol 2010 Apr;9(4):413–24.   [CrossRef]   [Pubmed]    Back to citation no. 22
  23. Lafrenière RG, Cader MZ, Poulin JF, et al. A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med 2010 Oct;16(10):1157–60.   [CrossRef]   [Pubmed]    Back to citation no. 23
  24. Clark JD, Tempel BL. Hyperalgesia in mice lacking the Kv1.1 potassium channel gene. Neurosci Lett 1998 Jul 24;251(2):121–4.   [CrossRef]   [Pubmed]    Back to citation no. 24
  25. Alloui A, Zimmermann K, Mamet J, et al. TREK-1, a K+ channel involved in polymodal pain perception. EMBO J 2006 Jun 7;25(11):2368–76.   [CrossRef]   [Pubmed]    Back to citation no. 25
  26. North RA. Molecular physiology of P2X receptors. Physiol Rev 2002 Oct;82(4):1013–67.   [CrossRef]   [Pubmed]    Back to citation no. 26
  27. Burnstock G. Purinergic P2 receptors as targets for novel analgesics. Pharmacol Ther 2006 Jun;110(3):433–54.   [CrossRef]   [Pubmed]    Back to citation no. 27
  28. Lingueglia E. Acid-sensing ion channels in sensory perception. J Biol Chem 2007 Jun 15;282(24):17325–9.   [CrossRef]   [Pubmed]    Back to citation no. 28
  29. Yan J, Edelmayer RM, Wei X, De Felice M, Porreca F, Dussor G. Dural afferents express acid-sensing ion channels: a role for decreased meningeal pH in migraine headache. Pain 2011 Jan;152(1):106–13.   [CrossRef]   [Pubmed]    Back to citation no. 29
  30. Huang D, Li S, Dhaka A, Story GM, Cao YQ. Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura. Mol Pain 2012 Sep 12;8:66.   [CrossRef]   [Pubmed]    Back to citation no. 30
  31. Sand CA, Grant AD, Nandi M. Vascular Expression of Transient Receptor Potential Vanilloid 1 (TRPV1). J Histochem Cytochem 2015 Jun;63(6):449–53.   [CrossRef]   [Pubmed]    Back to citation no. 31
  32. Zhang Z, Winborn CS, Marquez de Prado B, Russo AF. Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci 2007 Mar 7;27(10):2693–703.   [CrossRef]   [Pubmed]    Back to citation no. 32
  33. Ceruti S, Villa G, Fumagalli M, et al. Calcitonin gene-related peptide-mediated enhancement of purinergic neuron/glia communication by the algogenic factor bradykinin in mouse trigeminal ganglia from wild-type and R192Q Cav2.1 Knock-in mice: implications for basic mechanisms of migraine pain. J Neurosci 2011 Mar 9;31(10):3638–49.   [CrossRef]   [Pubmed]    Back to citation no. 33
  34. Burstein R, Yamamura H, Malick A, Strassman AM. Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol 1998 Feb;79(2):964–82.   [Pubmed]    Back to citation no. 34
  35. Cregg R, Momin A, Rugiero F, Wood JN, Zhao J. Pain channelopathies. J Physiol 2010 Jun 1;588(Pt 11):1897–904.   [CrossRef]   [Pubmed]    Back to citation no. 35
  36. Basbaum AI, Bautista DM, Scherrer G, Julius D. Julius D. Cellular and molecular mechanisms of pain. Cell 2009 Oct 16;139(2):267–84.   [CrossRef]   [Pubmed]    Back to citation no. 36
  37. Liang J, Liu X, Zheng J, Yu S. Effect of amitriptyline on tetrodotoxin-resistant Nav1.9 currents in nociceptive trigeminal neurons. Mol Pain 2013 Jun 22;9:31.   [CrossRef]   [Pubmed]    Back to citation no. 37
  38. Liang J, Liu X, Pan M, et al. Blockade of Nav1.8 currents in nociceptive trigeminal neurons contributes to anti-trigeminovascular nociceptive effect of amitriptyline. Neuromolecular Med 2014 Jun;16(2):308–21.   [CrossRef]   [Pubmed]    Back to citation no. 38
  39. Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998 Nov;44(5):731–9.   [CrossRef]   [Pubmed]    Back to citation no. 39
  40. Cleves C, Friedman NR, Rothner AD, Hussain MS. Genetically confirmed CADASIL in a pediatric patient. Pediatrics 2010 Dec;126(6):e1603–7.   [CrossRef]   [Pubmed]    Back to citation no. 40
  41. Yamamoto Y, Craggs LJ, Watanabe A, et al. Brain microvascular accumulation and distribution of the NOTCH3 ectodomain and granular osmiophilic material in CADASIL. J Neuropathol Exp Neurol 2013 May;72(5):416–31.   [CrossRef]   [Pubmed]    Back to citation no. 41
  42. Chen X, Xiao W, Wang W, Luo L, Ye S, Liu Y. The complex interplay between ERK1/2, TGFβ/Smad, and Jagged/Notch signaling pathways in the regulation of epithelial-mesenchymal transition in retinal pigment epithelium cells. PLoS One 2014 May 2;9(5):e96365.   [CrossRef]   [Pubmed]    Back to citation no. 42
  43. Liem MK, Oberstein SA, van der Grond J, Ferrari MD, Haan J. CADASIL and migraine: A narrative review. Cephalalgia 2010 Nov;30(11):1284–9.   [CrossRef]   [Pubmed]    Back to citation no. 43
  44. Richards A, van den Maagdenberg AM, Jen JC, et al. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 2007 Sep;39(9):1068–70.   [CrossRef]   [Pubmed]    Back to citation no. 44
  45. Xu Y, Padiath QS, Shapiro RE, et al. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 2005 Mar 31;434(7033):640–4.   [Pubmed]    Back to citation no. 45
  46. Tsai IC, Woolf M, Neklason DW, et al. Disease-associated casein kinase I delta mutation may promote adenomatous polyps formation via a Wnt/beta-catenin independent mechanism. Int J Cancer 2007 Mar 1;120(5):1005–12.   [Pubmed]    Back to citation no. 46
  47. Wood H. Genetics: expanding the spectrum of neurological disorders associated with PRRT2 mutations. Nat Rev Neurol 2012 Dec;8(12):657.   [CrossRef]   [Pubmed]    Back to citation no. 47
  48. Riant F, Roze E, Barbance C, et al. PRRT2 mutations cause hemiplegic migraine. Neurology 2012 Nov 20;79(21):2122–4.   [CrossRef]   [Pubmed]    Back to citation no. 48
  49. Stelzl U, Worm U, Lalowski M, et al. A human protein-protein interaction network: a resource for annotating the proteome. Cell 2005 Sep 23;122(6):957–68.   [CrossRef]   [Pubmed]    Back to citation no. 49
  50. Nyholt DR, LaForge KS, Kallela M, et al. A high-density association screen of 155 ion transport genes for involvement with common migraine. Hum Mol Genet 2008 Nov 1;17(21):3318–31.   [CrossRef]   [Pubmed]    Back to citation no. 50
  51. de Vries B, Anttila V, Freilinger T, et al. Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set. Cephalalgia 2015 Jan 29. pii: 0333102414566820.   [CrossRef]   [Pubmed]    Back to citation no. 51
  52. Zhu B, Ramachandran B, Gulick T. Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain. J Biol Chem 2005 Aug 5;280(31):28749–60.   [CrossRef]   [Pubmed]    Back to citation no. 52
  53. Lionel AC, Tammimies K, Vaags AK, et al. Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. Hum Mol Genet 2014 May 15;23(10):2752–68.   [CrossRef]   [Pubmed]    Back to citation no. 53
  54. Jarray R, Allain B, Borriello L, et al. Depletion of the novel protein PHACTR-1 from human endothelial cells abolishes tube formation and induces cell death receptor apoptosis. Biochimie 2011 Oct;93(10):1668–75.   [CrossRef]   [Pubmed]    Back to citation no. 54
  55. Frühbeck G, Sesma P, Burrell MA. PRDM16: the interconvertible adipo-myocyte switch. Trends Cell Biol 2009 Apr;19(4):141–6.   [CrossRef]   [Pubmed]    Back to citation no. 55
  56. Wu H, Chen Y, Miao S, et al. Sperm associated antigen 8 (SPAG8), a novel regulator of activator of CREM in testis during spermatogenesis. FEBS Lett 2010 Jul 2;584(13):2807–15.   [CrossRef]   [Pubmed]    Back to citation no. 56
  57. Zhao N, Koenig SN, Trask AJ, et al. MicroRNA miR145 regulates TGFBR2 expression and matrix synthesis in vascular smooth muscle cells. Circ Res 2015 Jan 2;116(1):23–34.   [CrossRef]   [Pubmed]    Back to citation no. 57
  58. Otsubo C, Otomo R, Miyazaki M, et al. TSPAN2 is involved in cell invasion and motility during lung cancer progression. Cell Rep 2014 Apr 24;7(2):527–38.   [CrossRef]   [Pubmed]    Back to citation no. 58
  59. Shofuda T, Shofuda K, Ferri N, Kenagy RD, Raines EW, Clowes AW. Cleavage of focal adhesion kinase in vascular smooth muscle cells overexpressing membrane-type matrix metalloproteinases. Arterioscler Thromb Vasc Biol 2004 May;24(5):839–44.   [CrossRef]   [Pubmed]    Back to citation no. 59
  60. Zeng L, Fee BE, Rivas MV, Lin J, Adamson DC. Adherens junctional associated protein-1: a novel 1p36 tumor suppressor candidate in gliomas (Review). Int J Oncol 2014 Jul;45(1):13–7.   [CrossRef]   [Pubmed]    Back to citation no. 60
  61. He Z, He M, Wang C, et al. Prognostic significance of astrocyte elevated gene-1 in human astrocytomas. Int J Clin Exp Pathol 2014 Jul 15;7(8):5038–44.   [Pubmed]    Back to citation no. 61
  62. Ruzali WA, Kehoe PG, Love S. Influence of LRP-1 and apolipoprotein E on amyloid-β uptake and toxicity to cerebrovascular smooth muscle cells. J Alzheimers Dis 2013;33(1):95–110.   [CrossRef]   [Pubmed]    Back to citation no. 62
  63. Emonard H, Théret L, Bennasroune AH, Dedieu S. Regulation of LRP-1 expression: make the point. Pathol Biol (Paris) 2014 Apr;62(2):84–90.   [CrossRef]   [Pubmed]    Back to citation no. 63
  64. Ferrari MD, Klever RR, Terwindt GM, Ayata C, van den Maagdenberg AM. Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurol 2015 Jan;14(1):65–80.   [CrossRef]   [Pubmed]    Back to citation no. 64

[HTML Abstract]   [PDF Full Text]

Author Contributions:
Wenjing Tang – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Shengyuan Yu – Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of submission
The corresponding author is the guarantor of submission.
Source of support
None
Conflict of interest
Authors declare no conflict of interest.
Copyright
© 2015 Wenjing Tang et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.