A Locus for Migraine without Aura Maps on Chromosome 14q21.2-q22.3
2003; Elsevier BV; Volume: 72; Issue: 1 Linguagem: Inglês
10.1086/345298
ISSN1537-6605
AutoresD. Soragna, Andrea Vettori, Gianni Carraro, Enrico Marchioni, Giovanni Vazza, Silvia Bellini, Rossella Tupler, F Savoldi, M.L. Mostacciuolo,
Tópico(s)Nicotinic Acetylcholine Receptors Study
ResumoMigraine is a common and disabling neurological disease of unknown origin characterized by a remarkable clinical variability. It shows strong familial aggregation, suggesting that genetic factors are involved in its pathogenesis. Different approaches have been used to elucidate this hereditary component, but a unique transmission model and causative gene(s) have not yet been identified. We report clinical and molecular data from a large Italian pedigree in which migraine without aura (MO) segregates as an autosomal dominant trait. After exclusion of any association between MO and the known familial hemiplegic migraine and migraine with aura loci, we performed a genomewide linkage analysis using 482 polymorphic microsatellite markers. We obtained significant evidence of linkage between the MO phenotype and the marker D14S978 on 14q22.1 (maximum two-point LOD score of 3.70, at a recombination fraction of 0.01). Multipoint parametric analysis (maximum LOD score of 5.25 between markers D14S976 and D14S978) and haplotype construction showed strong evidence of linkage in a region of 10 cM flanked by markers D14S1027 and D14S980 on chromosome 14q21.2-q22.3. These results indicate the first evidence of a genetic locus associated with MO on chromosome 14. Migraine is a common and disabling neurological disease of unknown origin characterized by a remarkable clinical variability. It shows strong familial aggregation, suggesting that genetic factors are involved in its pathogenesis. Different approaches have been used to elucidate this hereditary component, but a unique transmission model and causative gene(s) have not yet been identified. We report clinical and molecular data from a large Italian pedigree in which migraine without aura (MO) segregates as an autosomal dominant trait. After exclusion of any association between MO and the known familial hemiplegic migraine and migraine with aura loci, we performed a genomewide linkage analysis using 482 polymorphic microsatellite markers. We obtained significant evidence of linkage between the MO phenotype and the marker D14S978 on 14q22.1 (maximum two-point LOD score of 3.70, at a recombination fraction of 0.01). Multipoint parametric analysis (maximum LOD score of 5.25 between markers D14S976 and D14S978) and haplotype construction showed strong evidence of linkage in a region of 10 cM flanked by markers D14S1027 and D14S980 on chromosome 14q21.2-q22.3. These results indicate the first evidence of a genetic locus associated with MO on chromosome 14. Migraine (MIM 157300) is a complex and heterogeneous disease characterized by recurrent attacks of headache associated with autonomic and neurological symptoms, that affects ∼12% of the general population (Stewart et al. Stewart et al., 1992Stewart W Lipton R Celentano D Reed M Prevalence of migraine headache in the United States.JAMA. 1992; 267: 64-69Crossref PubMed Scopus (1486) Google Scholar). Diagnosis is based on clinical criteria, since biochemical or instrumental tests are not available (Headache Classification Committee of the International Headache Society [HCCIHS]Headache Classification Committee of the International Headache Society, 1988Headache Classification Committee of the International Headache Society Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.Cephalalgia. 1988; : S1-S96Google Scholar). Two primary types of migraine can be distinguished: migraine without aura (MO) and migraine with aura (MA). MO, the most common form of migraine, is characterized by unilateral pulsating headache of moderate to severe intensity, lasting 4–72 h. The attacks are associated with nausea, vomiting, and photo- and phonophobia and are aggravated by physical activity. In MA, headache attacks are preceded by transient focal neurological aura symptoms, which are usually visual. Frequency, duration, and severity of the attacks vary substantially among patients and also in the same patients. Moreover, these two forms of migraine can co-occur in up to 33% of migraineurs (Russell et al. Russell et al., 1995Russell MB Rasmussen BK Thornvaldsen P Olesen J Prevalence and sex-ratio of the subtypes of migraine.Int J Epidemiol. 1995; 24: 612-618Crossref PubMed Scopus (366) Google Scholar), but usually one type of attack prevails. The etiopathogenesis of migraine remains largely unknown. Neurophysiological and neurofunctional studies support a primary neuronal theory, according to which a neuronal hyperexcitability is the biological basis for susceptibility to migraine (Hargreaves and Shepheard Hargreaves and Shepheard, 1999Hargreaves RJ Shepheard SL Pathophysiology of migraine—new insights.Can J Neurol Sci. 1999; : S12-S19PubMed Google Scholar). Neuronal instability should be responsible for neuroelectric (Goadsby and Edvinsson Goadsby and Edvinsson, 1993Goadsby PJ Edvinsson L The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats.Ann Neurol. 1993; 33: 48-56Crossref PubMed Scopus (965) Google Scholar; Lauritzen et al. Lauritzen, 1994Lauritzen M Pathophysiology of migraine: the spreading depression theory.Brain. 1994; 117: 199-210Crossref PubMed Scopus (1029) Google Scholar) and metabolic events (Goadsby et al. Goadsby et al., 1990Goadsby PJ Edvinsson L Ekman R Vasoactive neuropeptide release in the extracerebral circulation of humans during migraine headache.Ann Neurol. 1990; 28: 183-187Crossref PubMed Scopus (1222) Google Scholar) leading to migraine attack. Familial clustering suggests that migraine has a significant genetic component, but the mode of inheritance remains unclear (Mochi et al. Mochi et al., 1993Mochi M Sangiorgi S Cortelli P Carelli V Scapoli C Crisci M Monari L Pierangeli G Montagna P Testing models for genetic determination of migraine.Cephalalgia. 1993; 13: 389-394Crossref PubMed Scopus (73) Google Scholar; Russell and Olesen Russell and Olesen, 1993Russell MB Olesen J The genetics of migraine without aura and migraine with aura.Cephalalgia. 1993; 13: 245-248Crossref PubMed Scopus (85) Google Scholar). Family-, twin-, and population-based studies strongly suggest that the two types of migraine are genetically determined, most likely with a multifactorial mode of inheritance (Honkasalo et al. Honkasalo et al., 1995Honkasalo ML Kaprio J Winter T Heikkila K Sillanpaa M Koskenvuo M Migraine and concomitant symptoms among 8167 adult twin pairs.Headache. 1995; 35: 70-78Crossref PubMed Scopus (146) Google Scholar; Stewart et al. Stewart et al., 1997Stewart WF Staffa J Lipton RB Ottman R Familial risk of migraine: a population-based study.Ann Neurol. 1997; 41: 166-172Crossref PubMed Scopus (142) Google Scholar; Gervil et al. Gervil et al., 1999Gervil M Ulrich V Kyvik KO Olesen J Russell MB Migraine without aura: a population-based twin study.Ann Neurol. 1999; 46: 606-611Crossref PubMed Scopus (111) Google Scholar; Ulrich et al. Ulrich et al., 1999Ulrich V Gervil M Kyvik K Olesen J Russell MB Evidence of a genetic factor in migraine with aura: a population-based Danish twin study.Ann Neurol. 1999; 45: 242-246Crossref PubMed Scopus (189) Google Scholar). However, in some families, a Mendelian pattern of inheritance cannot be excluded (Russell and Olesen Russell and Olesen, 1995Russell MB Olesen J Inheritance of migraine investigated by complex segregation analysis.Hum Genet. 1995; 96: 726-730Crossref PubMed Scopus (110) Google Scholar). At present, the only nosologic entity genetically characterized is familial hemiplegic migraine (FHM) (FHM1 [MIM 141500]), a rare autosomal dominantly inherited subtype of MA in which hemiplegia is the principal aura feature (HCCIHS Headache Classification Committee of the International Headache Society, 1988Headache Classification Committee of the International Headache Society Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.Cephalalgia. 1988; : S1-S96Google Scholar). It is considered a genetically heterogeneous disorder; half of the known families with FHM have been associated with mutations in the brain-specific P/Q type calcium channel alpha subunit (CACNA1A) located on 19p13 chromosome (MIM 601011) (Joutel et al. Joutel et al., 1993Joutel A Bousser MG Biousse V Labauge P Chabriat H Nibbio A Maciazek J Meyer B Bach MA Weissenbach J Lathrop GM Tournier-Lasserve E A gene for familial hemiplegic migraine maps to chromosome 19.Nat Genet. 1993; 5: 40-45Crossref PubMed Scopus (374) Google Scholar; Ophoff et al. Ophoff et al., 1996Ophoff RA Terwindt GM Vergouwe MN van Eijk R Oefner PJ Hoffman SM Lamerdin JE Mohrenweiser MW Bulman DE Ferrari M Haan J Linolhout D van Ommen GJ Hofker MH Ferrari MD Frants RR Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.Cell. 1996; 87: 543-552Abstract Full Text Full Text PDF PubMed Scopus (2116) Google Scholar; Ducros et al. Ducros et al., 2001Ducros A Denier C Joutel A Cecillon M Lescoat C Vahedi K Dracel F Vicaut E Bousser MG Tournier-Lasserve E The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.N Engl J Med. 2001; 345: 17-24Crossref PubMed Scopus (467) Google Scholar), and additional FHM linkage loci have been reported on chromosomes 1q21-q23 (FHM2 [MIM 602481]) (Ducros et al. Ducros et al., 1997Ducros A Joutel A Vahedi K Cecillon M Ferreira A Bernard E Verier A Echenne B Lopez de Manain A Bousser MG Tournier-Lasserve E Mapping of a second locus for familial hemiplegic migraine to 1q21–23 and evidence of further heterogeneity.Ann Neurol. 1997; 42: 885-890Crossref PubMed Scopus (204) Google Scholar) and on 1q31 (Gardner et al. Gardner et al., 1997Gardner K Barmada M Ptacek LJ Hoffman EP A new locus for hemiplegic migraine maps to chromosome 1q31.Neurology. 1997; 49: 1231-1238Crossref PubMed Scopus (178) Google Scholar). FHM can be considered part of the migraine spectrum and, thus, it has been used as a model to study the complex genetics of the common forms of migraine. Nevertheless, the role of 19p FHM locus in MO and MA is still debated (May et al. May et al., 1995May A Ophoff RA Terwindt GM Urban C van Eijk R Haan J Diener HC Lindhout D Frants RR Sandkuijl LA Ferrari MD Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura.Hum Genet. 1995; 96: 604-608Crossref PubMed Scopus (177) Google Scholar; Hovatta et al. Hovatta et al., 1994Hovatta I Kallela M Färkkilä M Peltonen L Familial migraine: exclusion of the susceptibility gene from the reported locus of familial hemiplegic migraine on 19p.Genomics. 1994; 23: 707-709Crossref PubMed Scopus (84) Google Scholar; Nyholt et al. Nyholt et al., 1998Nyholt DR Lea R Goadsby P Brimage P Griffiths L Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity.Neurology. 1998; 50: 1428-1432Crossref PubMed Scopus (129) Google Scholar). In familial typical migraine, linkage to 1q31 FHM locus (Lea et al. Lea et al., 2002Lea RA Shepherd AG Curtain RP Nyholt DR Quinlan S Brimage PJ Griffiths LR A typical migraine susceptibility region localizes to chromosome 1q31.Neurogenetics. 2002; 4: 17-22Crossref PubMed Scopus (67) Google Scholar) and to chromosome Xq24-q28 was recently established (MFTS [MIM 300125]) (Nyholt et al. Nyholt et al., 2000Nyholt DR Curtain RP Griffiths LR Familial typical migraine: significant linkage and localization of a gene to Xq24-28.Hum Genet. 2000; 107: 18-23PubMed Google Scholar). Moreover, a new locus on chromosome 19p13, distinct from the CACNA1A gene, was found to be linked to MA (Jones et al. Jones et al., 2001Jones KW Ehm MG Pericak-Vance MA Haines JL Boyd PR Peroutka SJ Migraine with aura susceptibility locus on chromosome 19p13 is distinct from the familial hemiplegic migraine locus.Genomics. 2001; 78: 150-154Crossref PubMed Scopus (62) Google Scholar), and a susceptibility locus for MA was identified on chromosome 4q24 (MGAU [MIM 300125]) by Wessman et al. (Wessman et al., 2002Wessman M Kallela M Kaunisto MA Marttila P Sobel E Hartiala J Oswell G Leal SM Papp JC Hämäläinen E Broas P Joslyn G Hovatta I Hiekkalinna T Kaprio J Ott J Cantor RM Zwart JA Ilmavirta M Havanka H Färkkilä M Peltonen L Palotie A A susceptibility locus for migraine with aura, on chromosome 4q24.Am J Hum Genet. 2002; 70: 652-662Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Genetic association studies have suggested linkage between different genetic loci and either MO or MA (Pardo et al. Pardo et al., 1995Pardo J Carracedo A Munoz I Castillo J Lema M Noya M Genetic markers: association study in migraine.Cephalalgia. 1995; 15: 200-204Crossref PubMed Scopus (21) Google Scholar; Peroutka et al. Peroutka et al., 1997Peroutka SJ Wilhoit T Jones K Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles.Neurology. 1997; 49: 201-206Crossref PubMed Scopus (163) Google Scholar; Ogilvie et al. Ogilvie et al., 1998Ogilvie AD Russell MB Dhall P Battersby S Ulrich V Smith CA Goodwin GM Harmar AJ Olesen J Altered allelic distribution of the serotonin transporter gene in migraine without aura and migraine with aura.Cephalalgia. 1998; 18: 23-26Crossref PubMed Scopus (94) Google Scholar; Lea et al. Lea et al., 2000Lea RA Dohy A Jordan K Quinlan S Brimage PJ Griffiths LR Evidence for allelic association of the dopamine β-hydroxylase gene (DBH) with susceptibility to typical migraine.Neurogenetics. 2000; 3: 35-40PubMed Google Scholar; McCarthy et al. McCarthy et al., 2001McCarthy LC Hosford DA Riley JH Bird MI White NJ Hewett DR Peroutka SJ et al.Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine.Genomics. 2001; 78: 135-149Crossref PubMed Scopus (115) Google Scholar, Tzourio et al. Tzourio et al., 2001Tzourio C El Amrani M Poirier O Nicaud V Bousser MG Alperovitch A Association between migraine and endothelin type A receptor (ETA −231 A/G) gene polymorphism.Neurology. 2001; 56: 1273-1277Crossref PubMed Scopus (109) Google Scholar), but the results of these studies often remain controversial and unconfirmed. Identification of genes predisposing to migraine has been complicated by clinical and genetic heterogeneity of the disease. However, studies of large pedigrees with a clear pattern of inheritance might be extremely useful in identifying genes involved in migraine pathogenesis. Here, we describe a large four-generation Italian family, originating from a restricted geographical area of northern Italy, in which MO appears to segregate as an autosomal dominant trait (fig. 1). After exclusion of any association between MO and the known FHM and MA loci, we performed a genomewide scan of the 22 autosomes to identify the putative genetic locus associated with MO. The propositus (III:10), a 49-year-old man, was the fourth child of nonconsanguineous parents. Since his adolescence, he complained of migraine attacks occurring once per wk. The attacks were characterized by severe pulsating unilateral headache lasting ⩾12 h, accompanied by nausea and photo- and phonophobia. Neither premonitory symptoms nor triggering factors typical for migraine nor neurological aura was reported. The common antimigraine agents resulted only in a partial and brief relief of pain, and prophylactic headache medication (propanolol and amitriptyline) had low efficacy. General examination was normal; neurological examination disclosed the presence of diffuse brisk deep tendon reflexes without asymmetry. Electroencephalogram (EEG) and brain CT scan were within normal limits. Family history revealed that other family members suffered recurrent migraine attacks. A total of 33 subjects (27 family members and 6 spouses) were evaluated by a certified neurologist. Clinical evaluation included extensive history and physical and neurological examination. EEG and CT scan were performed in five individuals (II:6, III:5, III:7, III:12, and III:16). When HCCIHS (Headache Classification Committee of the International Headache Society, 1988Headache Classification Committee of the International Headache Society Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.Cephalalgia. 1988; : S1-S96Google Scholar) criteria were used for diagnosing MO, 22 subjects were categorized as affected and 11 as unaffected (fig. 1). Among the 22 MO subjects, clinical features were almost homogeneous; attacks were characterized by moderate–severe pulsating unilateral headache lasting from a few hours to some days and accompanied by nausea and/or photo- and phonophobia. Migraine attack frequency was variable, from 1–2 attacks per mo to 2–3 attacks per wk. Two subjects (III:5 and III:16) occasionally experienced migraine attacks preceded by visual aura lasting a few minutes in addition to high frequency (>1 per wk) of MO attacks. In particular, subject III:5, who was affected with borderline hypertension, experienced two episodes of migraine with visual aura; individual III:16 presented only one attack of migraine with visual aura. We think that the isolated occurrence of MA attacks does not change the diagnosis of MO in these subjects. Disease onset was during childhood or adolescence in all individuals. All subjects were normal at the physical examination, although neurological examination disclosed the presence of a diffuse hyperactivity of the muscle stretch reflexes in eight affected individuals (II:6, III:5, III:7, III:8, III:10, III:12, IV:5, and IV:9). EEG and brain CT scan were within normal limits in the examined subjects. We obtained informed consent from 21 subjects affected with MO and 3 unaffected subjects (1 family member, IV:7, and 2 spouses, II:5 and III:6), on whom we performed molecular analyses. Venous blood samples were used to extract genomic DNA and to establish permanent lymphoblastoid cell lines according to standard techniques. First, we selected microsatellite markers from the putative candidate regions for FHM and MA on chromosomes 19p13, 1q21-23, 1q31, and 4q24. For these analyzed markers, we obtained two-point LOD score values 3.3, with a maximum two-point LOD score value of 3.70 at θ=0.01 for marker D14S978 (table 1).Table 1Two-Point LOD Scores for Migraine without Aura (MO) and Microsatellite Markers on Chromosome 14qLOD at θ =Marker.00.01.05.10.20.30.40D14S75−1.42−.70.17.47.54.35.11D14S1048−2.45−1.24.341.001.291.05.56D14S2881.762.202.702.762.381.70.82D14S10272.472.542.612.512.041.39.63D14S10683.563.613.593.382.731.89.90D14S9763.533.573.543.322.651.81.85D14S9783.653.703.683.462.791.93.92D14S1392.762.822.852.702.191.50.69D14S2762.312.382.442.331.891.29.58D14S9801.511.942.452.522.171.54.73 Open table in a new tab Multipoint analysis was performed by the FASTMAP program (Curtis et al. Curtis and Gurling, 1993Curtis D Gurling H A procedure for combining two-point lod scores into a summary multipoint map.Hum Hered. 1993; 43: 173-185Crossref PubMed Scopus (38) Google Scholar), using intermarker genetic distances based on the sex-averaged distances reported by the Genetic Location Database. Multipoint linkage LOD score provided strong evidence of linkage between markers D14S1027 and D14S980, with a peak of 5.25 between D14S976 and D14S978 (fig. 2). The most likely haplotype cosegregating with the disease is displayed in figure 1 along with the pedigree. The upper and lower limits of the critical region were established by the recombination events occurring in individual IV:10 (between markers D14S1027 and D14S68) and individual III:4 (between markers D14S276 and D14S980) (fig. 1). Our results provide strong evidence of an MO susceptibility locus on chromosome 14q21.2-14q22.3 within a 10-cM interval flanked by markers D14S1027 and D14S980. Statistically significant evidence of linkage was obtained with a parametric two-point linkage analysis and was supported by multipoint analyses. We chose to perform a parametric linkage analysis, since, in this family, MO segregates as an autosomal trait and presents with homogenous clinical features; therefore, it was plausible that a unique genetic defect contributes to risk of MO. Among the affected individuals, only III:7 does not share the affected haplotype and still presents with MO. Considering the high prevalence of migraine in the population and its complex etiology, subject III:7 may represent a phenocopy. According to the UCSC Human Genome Project Working Draft database, the flanking markers D14S1027 and D14S980 span a 12-Mb candidate region, which contains 45 known genes and >100 predicted genes. To better refine the disease haplotype, SNPs in the known genes can be used. Moreover, the collection of other affected family members can be useful to identify more recombinations to further narrow the region. Meanwhile, interesting candidate genes will be screened according to their expression profiles, function, and possible involvement in MO pathogenesis. Recently, several association genetic studies reported a possible association between different gene polymorphisms and either MA or MO. On the basis of these studies, neurotransmitter receptors (Peroutka et al. Peroutka et al., 1997Peroutka SJ Wilhoit T Jones K Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles.Neurology. 1997; 49: 201-206Crossref PubMed Scopus (163) Google Scholar; Del Zompo et al. Del Zompo et al., 1998Del Zompo M Cherchi A Palmas MA Ponti M Bocchetta A Gessa GL Piccardi MP Association between dopamine receptor genes and migraine without aura in a Sardinian sample.Neurology. 1998; 51: 781-786Crossref PubMed Scopus (121) Google Scholar; Ogilvie et al. Ogilvie et al., 1998Ogilvie AD Russell MB Dhall P Battersby S Ulrich V Smith CA Goodwin GM Harmar AJ Olesen J Altered allelic distribution of the serotonin transporter gene in migraine without aura and migraine with aura.Cephalalgia. 1998; 18: 23-26Crossref PubMed Scopus (94) Google Scholar; Lea et al. Lea et al., 2000Lea RA Dohy A Jordan K Quinlan S Brimage PJ Griffiths LR Evidence for allelic association of the dopamine β-hydroxylase gene (DBH) with susceptibility to typical migraine.Neurogenetics. 2000; 3: 35-40PubMed Google Scholar), vasoconstrictor receptors, (Tzourio et al. Tzourio et al., 2001Tzourio C El Amrani M Poirier O Nicaud V Bousser MG Alperovitch A Association between migraine and endothelin type A receptor (ETA −231 A/G) gene polymorphism.Neurology. 2001; 56: 1273-1277Crossref PubMed Scopus (109) Google Scholar), ion channel genes (May et al. May et al., 1995May A Ophoff RA Terwindt GM Urban C van Eijk R Haan J Diener HC Lindhout D Frants RR Sandkuijl LA Ferrari MD Familial hemiplegic migraine locus on 19p13 is involved in the common forms of migraine with and without aura.Hum Genet. 1995; 96: 604-608Crossref PubMed Scopus (177) Google Scholar; Terwindt et al. Terwindt et al., 2001Terwindt GM Ophoff RA van Eijk R Vergouwe MN Haan J Frants RR Sandkuijl LA Ferrari MD Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura.Neurology. 2001; 56: 1028-1032Crossref PubMed Scopus (123) Google Scholar), and the INSR gene (McCarthy et al. McCarthy et al., 2001McCarthy LC Hosford DA Riley JH Bird MI White NJ Hewett DR Peroutka SJ et al.Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine.Genomics. 2001; 78: 135-149Crossref PubMed Scopus (115) Google Scholar) can be considered good candidates for migraine. Even if no genes with such features were present within the chromosomal region we have identified, there are some genes that can be related to migraine pathogenesis. At present, on the basis of their function and their expression profiles, probable candidate genes are the GTP cyclohydrolase 1 gene (GCH1 [MIM 600225]) and the atlastin gene (SPG3A [MIM 606439]). Mutations in these genes have been identified in Dopa-responsive dystonia (Ichinose et al. Ichinose et al., 1994Ichinose H Ohye T Takahashi E Seki N Hori T Segawa M Nomura Y Endo K Tanaka H Tsuji S Fujita K Nagatsu T Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene.Nat Genet. 1994; 8: 236-242Crossref PubMed Scopus (702) Google Scholar) and spastic paraparesis (Zhao et al. Zhao et al., 2001Zhao X Alvarado D Rainier S Lemons R Hedera P Weber CH Tukel T Apak M Heiman-Patterson T Ming L Bui M Fink JK Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.Nat Genet. 2001; 29: 326-331Crossref PubMed Scopus (295) Google Scholar), respectively. Both of these genes are expressed in the CNS. SPG3A encodes a peptide showing homology with several GTPases that are involved in neurotransmission (Zhao et al. Zhao et al., 2001Zhao X Alvarado D Rainier S Lemons R Hedera P Weber CH Tukel T Apak M Heiman-Patterson T Ming L Bui M Fink JK Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.Nat Genet. 2001; 29: 326-331Crossref PubMed Scopus (295) Google Scholar), whereas GCH1 encodes GTP cyclohydrolase I, which catalyzes the rate-limiting step of tetrahydrobiopterin (Witter et al. Witter et al., 1996Witter K Werner T Blusch JH Schneider EM Riess O Ziegler I Rödl W Bacher A Gütlich M Cloning, sequencing and functional studies of the gene encoding human GTP cyclohydrolase I.Gene. 1996; 171: 285-290Crossref PubMed Scopus (27) Google Scholar), cofactor of tyrosine and tryptophan hydroxylases, and nitric oxide synthase (Werner et al. Werner et al., 1996Werner ER Werner-Felmayer G Wachter H Mayer B Biosynthesis of nitric oxide: dependence on pteridine metabolism.Rev Physiol Biochem Pharmacol. 1996; 127: 97-135Crossref PubMed Google Scholar). The latter three are involved in the production of dopamine, serotonin, and nitric oxide, which are implicated in migraine pathogenesis (Hargreaves and Shepheard Hargreaves and Shepheard, 1999Hargreaves RJ Shepheard SL Pathophysiology of migraine—new insights.Can J Neurol Sci. 1999; : S12-S19PubMed Google Scholar). Moreover, prostaglandin D2 receptor (PTGDR [MIM 606687]) and prostaglandin E receptor 2 genes (PTGER2 [MIM 176804]), which are implicated in inflammatory processes and in pain responses (Funk et al. Funk, 2001Funk CD Prostaglandins and leukotrienses: advances in ecosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (3039) Google Scholar), can be considered candidate genes. The bone morphogenetic protein 4 gene (BMP4 [MIM 112262]) encodes a cytokine belonging to the transforming growth factor-β superfamily and is implicated in the expression of the neuropeptide calcitonin gene-related protein (Ai et al. Ai et al., 1999Ai X Cappuzzello J Hall AK Activin and bone morphogenetic proteins induce calcitonin gene-related peptide in embryonic sensory neurons in vitro.Mol Cell Neurosci. 1999; 14: 506-518Crossref PubMed Scopus (61) Google Scholar), which mediates pain sensation and vasodilation (Goadsby et al. Goadsby et al., 1990Goadsby PJ Edvinsson L Ekman R Vasoactive neuropeptide release in the extracerebral circulation of humans during migraine headache.Ann Neurol. 1990; 28: 183-187Crossref PubMed Scopus (1222) Google Scholar). In summary, we have identified an MO-susceptibility locus on chromosomes 14q21.2–14q22.3. Further studies are required to identify the causative MO gene in this family and to delineate the role of this locus in other families affected with MO. The detection of genes involved in MO will allow the dissection of molecular mechanisms underlying migraine attacks to aid in diagnosis and to develop rational therapeutic tools. This study was supported by Telethon Grant E.1252. We are grateful to the family who participated in this study. We thank Dr. F. Pampinella for her constructive criticism and helpful discussion during this study. We thank Dr. I. Ranzini for her secretarial support. A special thanks to the Riquier family, who supported D.S. in performing the research.
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