Chiari malformation type I: a case-control association study of 58 developmental genes

Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A) considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI

Two-stage case-control association study of dopamine-related genes and migraine

Background We previously reported risk haplotypes for two genes related with serotonin and dopamine metabolism: MAOA in migraine without aura and DDC in migraine with aura. Herein we investigate the contribution to migraine susceptibility of eight additional genes involved in dopamine neurotransmission. Methods We performed a two-stage case-control association study of 50 tag single nucleotide polymorphisms (SNPs), selected according to genetic coverage parameters. The first analysis consisted of 263 patients and 274 controls and the replication study was composed by 259 cases and 287 controls. All cases were diagnosed according to ICHD-II criteria, were Spanish Caucasian, and were sex-matched with control subjects. Results Single-marker analysis of the first population identified nominal associations of five genes with migraine. After applying a false discovery rate correction of 10%, the differences remained significant only for DRD2 (rs2283265) and TH (rs2070762). Multiple-marker analysis identified a five-marker T-C-G-C-G (rs12363125-rs2283265-rs2242592-rs1554929-rs2234689) risk haplotype in DRD2 and a two-marker A-C (rs6356-rs2070762) risk haplotype in TH that remained significant after correction by permutations. These results, however, were not replicated in the second independent cohort. Conclusion The present study does not support the involvement of the DRD1, DRD2, DRD3, DRD5, DBH, COMT, SLC6A3 and TH genes in the genetic predisposition to migraine in the Spanish population

A causal effects of gut microbiota in the development of migraine

Background: The causal association between the gut microbiome and the development of migraine and its subtypes remains unclear. Methods: The single nucleotide polymorphisms concerning gut microbiome were retrieved from the gene-wide association study (GWAS) of the MiBioGen consortium. The summary statistics datasets of migraine, migraine with aura (MA), and migraine without aura (MO) were obtained from the GWAS meta-analysis of the International Headache Genetics Consortium (IHGC) and FinnGen consortium. Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. Results: In IHGC datasets, ten, five, and nine bacterial taxa were found to have a causal association with migraine, MA, and MO, respectively, (IVW, all P < 0.05). Genus.Coprococcus3 and genus.Anaerotruncus were validated in FinnGen datasets. Nine, twelve, and seven bacterial entities were identified for migraine, MA, and MO, respectively. The causal association still exists in family.Bifidobacteriaceae and order.Bifidobacteriales for migraine and MO after FDR correction. The heterogeneity and pleiotropy analyses confirmed the robustness of IVW results. Conclusion: Our study demonstrates that gut microbiomes may exert causal effects on migraine, MA, and MO. We provide novel evidence for the dysfunction of the gut-brain axis on migraine. Future study is required to verify the relationship between gut microbiome and the risk of migraine and its subtypes and illustrate the underlying mechanism between them

A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis

Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca2+ channel α1A subunit (CACNA1A) locate to the pore and voltage sensor regions and normally involve gain-of-channel function. We now report on a mutation identified in the first intracellular loop of CACNA1A (α1A(A454T)) that does not cause FHM but is associated with the absence of sensorimotor symptoms in a migraine with aura pedigree. α1A(A454T) channels showed weakened regulation of voltage-dependent steady-state inactivation by CaVβ subunits. More interestingy, A454T mutation suppressed P/Q channel modulation by syntaxin 1A or SNAP-25 and decreased exocytosis. Our findings reveal the importance of I-II loop structural integrity in the functional interaction between P/Q channel and proteins of the vesicle-docking/fusion machinery, and that genetic variation in CACNA1A may be not only a cause but also a modifier of migraine phenotype

GNAO1 encephalopathy : further delineation of a severe neurodevelopmental syndrome affecting females

De novo heterozygous mutations in the GNAO1 gene, encoding the Gα o subunit of G-proteins, are the cause of a severe neurodevelopmental disorder, featuring early infantile seizures, profound cognitive dysfunction and, occasionally, movement disorder (early infantile epileptic encephalopathy-17). We report a further case of this association in a 20 month-old Spanish girl with neonatal-onset refractory seizures, progressive microcephaly, oral-lingual dyskinesia and nearly absent psychomotor development. We performed whole-exome sequencing, a computational structural analysis of the novel gene variant identified and reviewed the previously reported cases. Trio whole-exome-sequencing uncovered a de novo p.Leu199Pro GNAO1 mutation. Computational structural analysis indicates this novel variant adversely affects the stability of the G-protein heterotrimeric complex as a whole. Of note, our patient showed a sustained seizure reduction while on a ketogenic diet. With this observation, a total of twelve patients with GNAO1 encephalopathy have been reported. Oral-lingual dyskinesia and responsiveness of seizures to ketogenic diet are novel features. The distorted sex ratio (12/12 females) of the condition remains unexplained; a differential gender effect of the disruption of G-protein- mediated signal transduction on the developing brain can be hypothesized. The online version of this article (doi:10.1186/s13023-016-0416-0) contains supplementary material, which is available to authorized users

Anàlisi genètica i molecular de les migranyes hereditàries

[cat] La migranya és un mal de cap primari, episòdic crònic i incapacitant molt comú a la població. Ha estat identificada per la Organització Mundial de la Salut (OMS) entre les principals causes d'incapacitat. La migranya té una etiologia complexa, amb contribució de múltiples gens d'efecte menor i factors ambientals que conjuntament determinen una certa predisposició a la patologia. No obstant, hi ha formes rares de migranya en què la causa és monogènica, amb un únic gen d'efecte major que determina l'aparició del fenotip. L'objectiu principal d'aquest treball ha estat aprofundir en l'estudi de la base genètica de les formes monogèniques de migranya i més específicament, identificar nous loci responsables del fenotip migranyós i nous al.lels mutats en gens ja reconeguts com a responsables d'aquest trastorn genèticament heterogeni. D'una banda, s'ha mapat el gen responsable de la migranya, de forma independent, en dues famílies catalanes extenses no emparentades, amb una herència dominant, a la regió cromosòmica 14q32. Tanmateix, la identificació del gen causant de la malaltia en aquestes famílies resta encara per resoldre. D'altra banda, s'han identificat 9 mutacions en el gen CACNA1A, totes elles de canvi de sentit, en individus espanyols amb diferents variants de migranya (HM, MA i CPS) i atàxia episòdica de tipus 2 (EA2). Tres de les mutacions són responsables del fenotip FHM, una de les quals es va identificar en un individu que manifestava símptomes de BPT i que va evolucionar a BPV i finalment a FHM. La quarta mutació es va trobar en un pacient que des dels 7 mesos de vida manifestava episodis d'hipotèrmia amb símptomes acompanyants i que podria correspondre a una variant, encara no ben caracteritzada clínicament, de CPS. S'han detectat dos canvis més en pacients amb manifestacions d'EA2. El setè canvi es va detectar en un pacient afectat d'EA2 i FHM, i el vuitè en un pacient amb EA2 i MA. La novena mutació s'ha identificat en dues pacients amb MA, mare i filla, que pertanyen a una família en què segrega FHM. En aquest darrer cas s'han pogut fer, en col·laboracio, estudis funcionals de la proteïna mutada, que revelen que determinades variacions en el gen CACNA1A poden tenir un paper modificador i no causant, com fins ara s'havia pensat, del fenotip migranyós. L'estudi de les formes monogèniques de migranya presenta diverses complicacions com l'heterogeneïtat genètica, la variabilitat en l'expressió clínica, la penetració incompleta, les fenocòpies i les genocòpies i l'efecte dels factors ambientals, el seu caràcter episòdic i la manca de marcadors biològics, la variabilitat de la simptomatologia en funció de l'edat de l'individu, la dificultat d'agrupar pacients en categories fenotípicament homogènies, la difícil obtenció del teixit d'interès -sistema nerviós central- i la dificultat d'interpretar i reproduir una simptomatologia basada en el testimoni del pacient, en animals d'experimentació. Els estudis de lligament que es presenten en aquest treball proporcionen evidències significatives de l'existència d'un nou locus comú a FHM i MA en dues famílies catalanes. La identificació d'un nou locus de migranya i els resultats de l'anàlisi mutacional realitzada en el gen CACNA1A augmenten la reconeguda heterogeneïtat genètica no al·lèlica i al·lèlica de les formes monogèniques i rares de migranya. Identificar el nou gen de migranya que hem localitzat al cromosoma 14 i estudiar la seva rellevància entre els pacients migranyosos a nivell espanyol i mundial contribuirà de ben segur a una millor comprensió dels mecanismes moleculars de la migranya i també a la identificació de possibles dianes terapèutiques en benefici dels pacients que la pateixen.[eng] Migraine is a chronic, episodic and disabling prymary headache. The World Health Organization (WHO) rated migraine among the most disabling chronic disorders. Migraine has a complex etiology involving multiple susceptibility genes and environmental factors. However, there are rare forms of migraine in which the cause is monogenic. The main goal of this work has been to study the genetic basis on the monogenic forms of migraine and more specifically, to identify new loci responsible for the migraine phenotype and new mutated alleles in genes responsibles for this genetically heterogeneous disorder. A gene responsible for migraine has been mapped in two extensive unrelated families at chr14q32. However, the identification of the causative gene rest to be identified. On the other hand, nine missense mutations have been identified in the CACNA1A gene in Spanish patients with hemiplegic migraine (HM), migraine with aura (MA), chilhood periodic syndromes (CPS) and episodic ataxia type 2 (EA2). Three of the mutations are responsible for the FHM phenotype, one of them was identified in an individual who manifested symptoms of childhood benign paroxysmal torticolis that evolved to benign paroxysmal vertigo and finally to FHM. The fourth mutation found in a patient that manifested episodes of hypothermia with accompanying symptoms, could correspond to a CPS variant. Two more changes have been detected in patients with EA2. The seventh change was detected in an affected patient of EA2 and FHM, and the eighth in a patient with EA2 and MA. The ninth mutation has been identified in two patients with MA belonging to a HM family. Functional studies of p.Ala454Thr CACNA1A protein revealed that some variants can have a not causative but modifier role. The linkage studies performed in this work provide significant evidence of the existence of a new common locus to FHM and MA. Its identification and the results of the mutational analysis carried out in CACNA1A gene increase the recognized genetic heterogeneity in monogenic forms of migraine. Identifying the new migraine gene will contribute to better understand the molecular mechanisms of migraine and the identication of new therapeutic targets

Chiari Malformation Type I: A Case-Control Association Study of 58 Developmental Genes

Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysi

Chiari malformation type I: a case-control association study of 58 developmental genes

Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A) considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI

Chiari Malformation Type I : a Case-Control Association Study of 58 Developmental Genes

Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A) considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI