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TREX1 in migraine and other neurovascular disorders

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Titel: High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice.
Auteur: van den Maagdenberg AM, Pizzorusso T, Kaja S, Terpolilli N, Shapovalova M, Hoebeek FE, Barrett CF, Gherardini L, van de Ven RC, Todorov B, Broos LA, Tottene A, Gao Z, Fodor M, De Zeeuw CI, Frants RR, Plesnila N, Plomp JJ, Pietrobon D, Ferrari MD.
Titel: Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Cav2.1 knocking migraine mice.
Auteur: Tottene A, Conti R, Fabbro A, Vecchia D, Shapovalova M, Santello M, van den Maagdenberg AMJM, Ferrari MD, Pietrobon D.
Titel: Genome-wide association study of migraine implicates a common variant on 8q22.1 regulating the expression of astrocyte elevated gene-1 (AEG-1).
Auteur: 22) Antilla V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS, Nyholt DR, Dimas AS, Freilinger T, Müller-Myhsok B, Artto V, Inouye M, Alakurtti K, Kaunisto MA, Hämäläinen E, De Vries B, Stam AH, Weller CM, Heinze A, Heinze-Kuhn K, Goebel I, Borck G, Göbel H, Steinberg S, Wolf C, Björnsson A, Gudmundsson G, Kirchmann M, Hauge A, Werge T, Schoenen J, Eriksson JG, Hagen K, Stovner L, Wichmann H-E, Meitinger T, Alexander M, Moebus S, Schreiber S, Aulchenko YS, Breteler MMB, Uitter
Titel: Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome.
Auteur: Munts AG, van der Plas AA, Ferrari MD, Teepe-Twiss IM, Marinus J, van Hilten JJ
Titel: Neuroimaging in trigeminal autonomic cephalalgias: when, how, and of what?
Auteur: Wilbrink LA, Ferrari MD, Kruit MC, Haan J.
Titel: Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis.
Auteur: Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG; Tonabersat TON-01-05 Study Group.
Titel: First mutation in the voltage-gated Nav1.1 subunit gene SCN1A with co-occurring familial hemiplegic migraine and epilepsy.
Auteur: Castro MJ, Stam AH, Lemos C, de Vries B, Vanmolkot KR, Barros J, Terwindt GM, Frants RR, Sequeiros J, Ferrari MD, Pereira-Monteiro JM, van den Maagdenberg AM.
Magazine: Cephalalgia
Titel: Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice.
Auteur: Eikermann-Haerter K, Baum MJ, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C.
Titel: TREX1 gene variant in neuropsychiatric systemic lupus erythematosus.
Auteur: de Vries B, Steup-Beekman GM, Haan J, Bollen EL, Luyendijk J, Frants RR, Terwindt GM, van Buchem MA, Huizinga TW, van den Maagdenberg AM, Ferrari MD.
Titel: Migraine in the Triptan Era: Lessons from epidemiology, pathophysiology, and clinical science.
Auteur: Bigal ME, Ferrari MD, Silberstein SD, Lipton RB, Goadsby PJ.
Titel: Early seizures and cerebral oedema after trivial head trauma associated with the CACNA1A S218L mutation.
Auteur: Stam AH, Luijckx GJ, Poll-Thé BT, Ginjaar IB, Frants RR, Haan J, Ferrari MD, Terwindt GM, van den Maagdenberg AM.
Titel: Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1.
Auteur: Anttila V, Stefansson H, Kallela M, Todt U, Terwindt GM, Calafato MS, Nyholt DR, Dimas AS, Freilinger T, Müller-Myhsok B, Artto V, Inouye M, Alakurtti K, Kaunisto MA, Hämäläinen E, de Vries B, Stam AH, Weller CM, Heinze A, Heinze-Kuhn K, Goebel I, Borck G, Göbel H, Steinberg S, Wolf C, Björnsson A, Gudmundsson G, Kirchmann M, Hauge A, Werge T, Schoenen J, Eriksson JG, Hagen K, Stovner L, Wichmann HE, Meitinger T, Alexander M, Moebus S, Schreiber S, Aulchenko YS, Breteler MM, Uitterlinden A
Magazine: Nature Genetics
Titel: Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice.
Auteur: Eikermann-Haerter K, Baum MJ, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C.
Titel: Randomized, double-blind, placebo-controlled, proof-of-concept study of the cortical spreading depression inhibiting agent tonabersat in migraine prophylaxis.
Auteur: Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG.
Titel: Migraine and genetic and acquired vasculopathies.
Auteur: Stam AH, Haan J, van den Maagdenberg AM, Ferrari MD, Terwindt GM.
Titel: A long-term follow-up study of 18 patients with sporadic hemiplegic migraine.
Auteur: Stam AH, Louter MA, Haan J, de Vries B, van den Maagdenberg AM, Frants RR, Ferrari MD, Terwindt GM
Titel: CACNA1A mutation linking hemiplegic migraine and alternating hemiplegia of childhood.
Auteur: de Vries B, Stam AH, Beker F, van den Maagdenberg AM, Vanmolkot KR, Laan L, Ginjaar IB, Frants RR, Lauffer H, Haan J, Haas JP, Terwindt GM, Ferrari MD.
Magazine: Cephalalgia
Titel: Shared genetic factors in migraine and depression: evidence from a genetic isolate.
Auteur: Stam AH, de Vries B, Janssens AC, Vanmolkot KR, Aulchenko YS, Henneman P, Oostra BA, Frants RR, van den Maagdenberg AM, Ferrari MD, van Duijn CM, Terwindt GM.
Titel: Migraine and genetic and acquired vasculopathies.
Auteur: Stam AH, Haan J, van den Maagdenberg AM, Ferrari MD, Terwindt GM.
Magazine: Cephalalgia
Titel: Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation: the population-based MRI CAMERA study.
Auteur: Kruit M, van Buchem M, Launer L, Terwindt G, Ferrari M.
Titel: MRI correlates of cognitive decline in CADASIL: A 7-year follow-up study.
Auteur: Liem MK, Lesnik Oberstein SAJ, Haan J, van der Neut IL, Ferrari MD, van Buchem MA, Middelkoop HAM, van der Grond J.
Titel: CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine
Auteur: Stam AH, Vanmolkot KR, Kremer HP, Gärtner J, Brown J, Leshinsky-Silver E, Gilad R, Kors EE, Frankhuizen WS, Ginjaar HB, Haan J, Frants RR, Ferrari MD, van den Maagdenberg AM, Terwindt GM.
Magazine: Clinical Genetics
Titel: Migraine and olcegepant
Auteur: Ho TW, Ferrari MD, Dodick DW, Kost J, Winner P.
Titel: No indication for patent foramen ovale closure in migraine.
Auteur: Koppen H, Terwindt GM, Haan J, de Bruijn SF, Bax JJ, Ferrari MD.
Titel: Familial hemiplegic migraine is associated with febrile seizures in an FHM2 family with a novel de novo ATP1A2 mutation.
Auteur: de Vries B, Stam AH, Kirkpatrick M, Vanmolkot KR, Koenderink JB, van den Heuvel JJ, Stunnenberg B, Goudie D, Shetty J, Jain V, van Vark J, Terwindt GM, Frants RR, Haan J, van den Maagdenberg AM, Ferrari MD.
Magazine: Epilepsia
Titel: Coding of facial expressions of pain in the laboratory mouse.
Auteur: Langford DJ, Bailey AL, Chanda ML, Clarke SE, Drummond TE, Echols S, Glick S, Ingrao J, Klassen-Ross T, Lacroix-Fralish ML, Matsumiya L, Sorge RE, Sotocinal SG, Tabaka JM, Wong D, van den Maagdenberg AM, Ferrari MD, Craig KD, Mogil JS.
Titel: Head tremor related to CACNA1A mutations
Auteur: Geerlings RP, Koehler PJ, Haane DY, Stam AH, de Vries B, Boon EM, Haan J.
Magazine: Cephalalgia
Titel: Brief report. Space headache: a new secondary headache.
Auteur: Vein AA, Koppen H, Haan J, Terwindt GM, Ferrari MD.
Titel: De potentiële rol van CGRP-receptorantagonisten in de behandeling van migraine; een blik in de nabije toekomst.
Auteur: Van Oosterhout WPJ, Maassen van den Brink A, Terwindt GM, Ferrari MD.
Titel: Migraine in the triptan era: lessons from epidemiology, pathophysiology, and clinical science.
Auteur: Bigal ME, Ferrari M, Silberstein SD, Lipton RB, Goadsby PJ.
Titel: Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1.
Auteur: Eikermann-Haerter, K, Dilekoz, E, Kudo C, Savitz SI, Waeber C, Baum MJ, Ferrari MD, Van den Maagdenberg AM, Moskowitz MA, Ayata C.
Titel: Episodic Ataxia associated with EAATI mutation C186S affecting glutamate reuptake.
Auteur: De Vries B, Mamsa H, Stam AH, Wan J, Bakker SLM, Vanmolkot KRJ, Haan J, Terwindt GM, Boon EMJ, Howard BD, Frants RR, Baloh RW, Ferrari MD, Jen JC, van den Maagdenberg AMJM.
Titel: Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake.
Auteur: de Vries B, Mamsa H, Stam AH, Wan J, Bakker SL, Vanmolkot KR, Haan J, Terwindt GM, Boon EM, Howard BD, Frants RR, Baloh RW, Ferrari MD, Jen JC, van den Maagdenberg AM.
Magazine: Archives of Neurology
Titel: Genetics of migraine: an update with special attention to genetic comorbidity
Auteur: Stam AH, van den Maagdenberg AM, Haan J, Terwindt GM, Ferrari MD.
Magazine: Current Opinion in Neurology
Titel: Shared genetic factors in migraine and depression: evidence from a genetic isolate.
Auteur: Stam AH, de Vries B, Janssens AC, Vanmolkot KR, Aulchenko YS, Henneman P, Oostra BA, Frants RR, van den Maagdenberg AM, Ferrari MD, van Duijn CM, Terwindt GM.
Magazine: Neurology
Titel: Quantitative cortical synapse proteomics of a transgenic migraine mouse model with mutated Ca(V)2.1 calcium channels.
Auteur: Klychnikov OI, Li KW, Sidorov IA, Loos M, Spijker S, Broos LA, Frants RR, Ferrari MD, Mayboroda OA, Deelder AM, Smit AB, van den Maagdenberg AM.
Titel: A long-term follow-up study of 18 patients with sporadic hemiplegic migraine.
Auteur: Stam AH, Louter MA, Haan J, de Vries B, van den Maagdenberg AM, Frants RR, Ferrari MD, Terwindt GM.
Magazine: Cephalalgia
Titel: Acute treatment of migraine with the selective 5-HT IF receptor agonist lasmiditan - A randomized proof-of-concept trial.
Auteur: Ferrari MD, Färkkilä M, Reuter U, Pilgrim A, Davis Ch, Krauss M, Diener H-C.
Titel: Early seizures and cerebral oedema after trivial head trauma associated with the CACNA1A S218L mutation.
Auteur: Stam AH, Luijckx GJ, Poll-Thé BT, Ginjaar IB, Frants RR, Haan J, Ferrari MD, Terwindt GM, van den Maagdenberg AM.
Magazine: Journal of Neurology, Neurosurgery and Psychiatry
Titel: Validation of the web-based LUMINA questionnaire for recruiting large cohorts of migraineurs.
Auteur: van Oosterhout WP, Weller CM, Stam AH, Bakels F, Stijnen T, Ferrari MD, Terwindt GM
Titel: Metabolic profiling of ultrasmall sample volumes with GC/MS: from microliter to nanoliter samples.
Auteur: Koek MM, Bakels F, Engel W, van den Maagdenberg A, Ferrari MD, Coulier L, Hankemeier T.

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Eindverslag

In 2007 werd het causale gen voor AD-RVCL (Autosomaal Dominante Retinale Vasculopathie met Cerebrale Leukodystrofie, OMIM:192315) ontdekt: het TREX1 gen. Dit gen codeert voor een 3’-5’ DNA exonuclease. AD-RVCL werd, voor de ontdekking van het gen, beschreven onder verschillende ziektenamen, namelijk “cerebroretinal vasculopathy” (CRV), “hereditary vascular retinopathy” (HVR) en “hereditary endotheliopathy, retinopathy, nephropathy and stroke” (HERNS).
In deze studie is het klinisch spectrum van AD-RVCL onderzocht en de genotype-phenotype correlatie geëvalueerd. Daarvoor is klinisch, radiologisch en pathologisch materiaal van 78 mutatiedragers uit 11 AD-RVCL families verzameld. De belangrijkste bevinding is dat, ondanks het feit dat AD-RVCL eerder onder verschillende ziektenamen werd beschreven, nu blijkt dat verschillende TREX1 mutaties tot eenzelfde klinisch beeld leiden, met weinig genotype specifieke manifestaties. De meeste patiënten hadden een vasculaire retinopathie. Deze mensen had meestal ook cerebrale symptomen, waaronder focaal neurologische uitvalsverschijnselen, meestal in combinatie met cerebrale aankleurende ruimte innemende laesies, focale calcificaties and/of hyperintense witte stof afwijkingen, migraine, cognitieve en psychiatrische stoornissen. Daarnaast hadden vele mensen systemische symptomen waaronder nierfunctiestoornissen, verhoogde leverenzymen, hypertensie, Raynaud en anemie. De preklinische en vroege ziektemanifestaties zijn mild en aspecifiek. Moleculair diagnostische screening van het TREX1 gen werd opgezet. In patiënten met klinisch overlappende kenmerken met AD-RVCL werden mutaties geïdentificeerd. Zo werd er een mutatie gevonden in een patiënt met neuropsychiatrisch SLE. De relevantie van de geïdentificeerde mutaties wordt momenteel onderzocht. Een genetische associatie studie in migraine cohorten uit de algemene populatie liet geen grote rol van zogenoemde ”common variants” in het TREX1 gen bij migraine zien.

Samenvatting van de aanvraag

We recently identified TREX1, that encodes the major mammalian 3’-5’ DNA exonuclease, as the causal gene for Autosomal Dominant Retinal Vasculopathy with Cerebral Leukodystrophy (AD-RVCL, OMIM:192315) in two Dutch and seven foreign families. AD-RVCL is a new neurovascular syndrome mainly characterized by prominent retinal vasculopathy leading to blindness at middle age and a wide range of both cerebral and systemic symptoms, apparently depending on the site and nature of mutations within the TREX1 gene. These symptoms include migraine, cerebral infarcts, white matter lesions (WMLs), vascular dementia, liver and kidney dysfunction and Raynaud’s phenomenon. In some families, patients die early within 5 – 10 years after disease onset. TREX1 mutations may result in an aberrant response to oxidative stress and presumably altered reactivity and integrity of blood vessels causing the neurovascular symptoms. Migraine is a highly prevalent and disabling, multifactorial neurovascular disorder associated with increased risks of ischaemic stroke, cerebral WMLs and microvascular retinopathy. AD-RVCL can be considered as a new monogenic neurovascular “migraine syndrome” similar to Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). CADASIL is caused by NOTCH3 mutations and is characterized by symptoms remarkably similar to those of AD-RVCL. TREX1 appears an excellent candidate gene for common types of migraine, CADASIL-like neurovascular disorders without NOTCH3 mutations, other types of vascular dementia, ischaemic stroke, and systemic lupus erythomathosus with neuropsychiatric symptoms. Studying the functional consequences of TREX1 mutations may improve the pathogenetic insight into AD-RVCL, migraine and the other neurovascular disorders. In the present proposal, we want to: i) establish a molecular diagnostic screening test for TREX1 and use this to identify new AD-RVCL patients; ii) screen patients with CADASIL-like diseases without Notch3 mutations for TREX1 mutations; iii) investigate the spectrum of neurovascular clinical, radiological, cognitive, and neuropathological manifestations associated with TREX1 mutations by performing detailed genotype-phenotype correlation studies in the currently available and new AD-RVCL families; iv) investigate the putative role of TREX1 in migraine by direct sequencing and case-control association studies. To address aims i) and ii) we will set up a reliable molecular test that is based on direct sequencing. The entire coding region of TREX1 can be analyzed with three overlapping PCR fragments. New AD-RVCL patients will be identified: a) by alerting Dutch ophthalmologists to refer unexplained retinopathy cases; and b) by screening patients with CADASIL-like neurovascular syndromes from the LUMC clinic for cerebrovascular hereditary angiopathies (CHITA) who do not have mutations in NOTCH3 or other known “neurovascular syndrome genes”. For aim iii) we will investigate penetrance and phenotypical (clinical, radiological, cognitive, pathological) and biochemical (Cerebrospinal Fluid) spectra in TREX1 mutation carriers. To address aim iv), we will use two complementary genetic approaches to investigate the ‘rare variant/common disease’ (RVCD) and the ‘common variant/common diseases’ (CVCD) hypotheses. The RVCD-hypothesis will be explored by direct sequencing for mutations in four populations: a) migraine with aura (n=200); b) migraine without aura (n=200); c) migrainous infarction (n>25); and d) migraine patients with CADASIL-like disease without NOTCH3 mutations (n>100). To investigate the CVCD hypothesis we will perform genetic association studies to test whether common variants in and around TREX1 contribute to migraine. To this end we have available several cohorts for the initial study. For subsequent replication and validation, we can make use of two German clinic-based samples (n=1100 and n=1065) plus age-and gender-matched German controls and a Dutch population-based sample (n=821 migraineurs and n=971 matched controls). From all Dutch persons, cardiovascular risk profiles are available and for a subset (n= 295 migraine and n=145 controls) MRI scans are available with known presence of vascular cerebral lesions, allowing for investigating the mediating effects of cardiovascular risk profiles and presence of MRI vascular lesions. We also have access to an extended, well defined (including cardiovascular risk profiles), family-based, Dutch genetic isolate (n=3465) including n=360 migraineurs. This sample can be used for genetic validation and to replicate association with cardiovascular risk factors. Genotyping will be performed at the LUMC using already operational TaqMan SNP genotyping assays.

Onderwerpen

Kenmerken

Projectnummer:
92003473
Looptijd: 100%
Looptijd: 100 %
2007
2011
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. M.D. Ferrari
Verantwoordelijke organisatie:
Leiden University Medical Center