Novel missense mutation in the ATP1A2 gene associated with atypical sporapedic hemiplegic migraine.
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ABSTRACT:
SUBMITTER: Rispoli MG
PROVIDER: S-EPMC6781968 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction. Familial hemiplegic migraine (FHM) is a rare disorder characterized by migraine attacks with motor weakness during the aura phase. Mutations in CACNA1A, ATP1A2, SCN1A, and PRRT2 genes have been described. Methods. To describe a mutation in ATP1A2 gene in a FHM case with especially severe and prolonged symptomatology. Results. 22-year-old woman was admitted due to migraine-type headache and sudden onset of right-sided weakness and aphasia; she had similar episodes in her childhood. Her mother was diagnosed with hemiplegic migraine without genetic confirmation. She presented with fever, decreased consciousness, left gaze preference, mixed aphasia, right facial palsy, right hemiplegia, and left crural paresis. Computed tomography (CT) showed no lesion and CT perfusion study evidenced oligohemia in left hemisphere. A normal brain magnetic resonance (MR) was obtained. Impaired consciousness and dysphasia began to improve three days after admission and mild dysphasia and right hemiparesis lasted for 10 days. No recurrences were reported during a follow-up of two years. We identified a variant in heterozygous state in ATP1A2 gene (p.Thr364Met), pathogenic according to different prediction algorithms (SIFT, PolyPhen2, MutationTaster, and Condel). Conclusion. Prolonged and severe attacks with diffuse hypoperfusion in a FHM seemed to be specially related to ATP1A2 mutations, and p.T364M should be considered.
| S-EPMC5081966 | biostudies-other
Project description:We describe the case of one patient with pure sporadic hemiplegic migraine (SHM) with a novel ATP1A2 gene variant and a large patent foramen ovale (PFO) with atrial septal aneurysm. In hemiplegic migraine (HM), the relationship between incomplete penetrance, environmental triggers, and phenotypic expression is underdetermined. A genetic evaluation of the proband was requested for the HM associated genes and extended to the members of his family. Genetic analysis revealed a never described before ATP1A2 gene mutation, inherited by his father, who never experienced motor aura but only typical visual aura. The proband-but not his father-was also affected by a large PFO with atrial septal aneurysm. SHM patient showed a marked reduction in motor aura episodes per year in the 12?months following the PFO percutaneous closure, followed by a complete remission from attacks at least in the following 24?months. We speculated that as well as incomplete penetrance of the novel mutation and natural history of the disease, an additional pathological condition such as the PFO could contribute to the phenotypical expression in this case of HM.
| S-EPMC5966544 | biostudies-literature
Project description:Hereditary sensorineural hearing loss is an extremely clinical and genetic heterogeneous disorder in humans. Especially, syndromic hearing loss is subdivided by combinations of various phenotypes, and each subtype is related to different genes. We present a new form of progressive hearing loss with migraine found to be associated with a variant in the ATP1A2 gene. The ATP1A2 gene has been reported as the major genetic cause of familial migraine by several previous studies. A Korean family presenting progressive hearing loss with migraine was ascertained. The affected members did not show any aura or other neurologic symptoms during migraine attacks, indicating on a novel phenotype of syndromic hearing loss. To identify the causative gene, linkage analysis and whole-exome sequencing were performed. A novel missense variant, c.571G>A (p.(Val191Met)), was identified in the ATP1A2 gene that showed co-segregation with the phenotype in the family. In silico studies suggest that this variant causes a change in hydrophobic interactions and thereby slightly destabilize the A-domain of Na(+)/K(+)-ATPase. However, functional studies failed to show any effect of the p.(Val191Met) substitution on the catalytic rate of this enzyme. We describe a new phenotype of progressive hearing loss with migraine associated with a variant in the ATP1A2 gene. This study suggests that a variant in Na(+)/K(+)-ATPase can be involved in both migraine and hearing loss.
| S-EPMC4402630 | biostudies-literature
Project description:Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing.
| S-EPMC3865589 | biostudies-literature
Project description:Sporadic Hemiplegic Migraine is a rare form of migraine headache. Mutations in three different genes, two ion-channel genes and one encoding an ATP exchanger, CACNA1A, ATP1A2 and SCN1A are all responsible for the FHM phenotype, thus indicating a genetic heterogeneity for this disorder. Here, we described a de novo exonic duplication of ATP1A2 in an Italian patient with Hemiplegic Migraine.We describe the case of a young woman (33 year old) who suffered from the age of 8 years of episodic weakness of the limbs, associated to other subjective and objective features. From aged 25, she developed neurological symptoms, like dizziness, blurred vision and an MRI scan revealed aspecific peritrigonal white matter hyperintensities. Aged 32 she suffered of right hemisomatic sudden-onset paresthesias, hypoesthesia and hyposthenia and the patient was genetically investigated for sporadic hemiplegic migraine.Here we report, for the first time, an exonic duplication in the ATP1A2 associated with hemiplegic migraine. The variation identified involves exon 21 of the ATP1A2 and is expected to alter the function of the alpha(2) subunit of the Na(+)/K(+) pump; the de novo nature of the duplication further supports its pathogenic role. To date, no other CNVs have been described in the ATP1A2 but only point mutations are reported. The novel mutation may result impaired M9 transmembrane domain, in a loss-of-function of the alpha(2) Na(+)/K(+)-ATPase with glutamate accumulation, alteration of synaptic function and neurotransmission.
| S-EPMC5462664 | biostudies-literature
Project description:Background and aimsHemiplegic migraine (HM) is a rare form of migraine characterized by the presence of a motor and other types of aura. HM can be sporadic or familial. Familial hemiplegic migraine (FHM) is an autosomal dominant disorder, classified into 3 subtypes, based on the gene involved (CACNA1A in FHM1, ATP1A2 in FHM2 and SCN1A in FHM3). The clinical presentation is highly heterogeneous and some attacks may be severe. We report the clinical characteristics and genetic analysis of 12 patients belonging to a family with CACNA1A-p.Thr501Met gene mutation.MethodsWe screened for mutations in CACNA1A gene 15 patients belonging to the same family. The exonic sequences of CACNA1A were analyzed using a Tru-seq® Custom Amplicon (TSCA) (Illumina Inc., San Diego, CA) targeted capture and paired end library kit. Sanger sequencing was used to confirm CACNA1A variants and segregation analysis.ResultsCACNA1A-p.Thr501Met mutation was found in 12 of the 15 patients screened, which was compatible with the diagnosis of FHM1. Attacks of hemiplegic migraine were reported by 10 of the 12 subjects (83.33%). Only one subject developed persistent mild cerebellar symptoms and none of the subjects developed cerebellar atrophy.DiscussionThe variant p.Thr501Met was described previously in association with episodic ataxia and rarely with FHM related to cerebellar symptoms. FHM1 has a broad clinical spectrum and about half of the families have cerebellar involvement. In our study, only one patient developed persistent cerebellar deficits. These data suggest that CACNA1A-p.Thr501Met mutation can occur prevalently as hemiplegic migraine.
| S-EPMC8317284 | biostudies-literature
Project description:BackgroundMutations in ATP1A2, the gene encoding the α2 subunit of Na+/K+-ATPase, are the main cause of familial hemiplegic migraine type 2 (FHM2). The clinical presentation of FHM2 with mutations in the same gene varies from pure FHM to severe forms with epilepsy and intellectual disability, but the correlation of these symptoms with different ATP1A2 mutations is still unclear.MethodsTen ATP1A2 missense mutations were selected according to different phenotypes of FHM patients. They caused pure FHM (FHM: R65W, R202Q, R593W, G762S), FHM with epilepsy (FHME: R548C, E825K, R938P), or FHM with epilepsy and intellectual disability (FHMEI: T378N, G615R, D718N). After ouabain resistance and fluorescence modification, plasmids carrying those mutations were transiently transfected into HEK293T and HeLa cells. The biochemical functions were studied including cell survival assays, membrane protein extraction, western blotting, and Na+/K+-ATPase activity tests. The electrophysiological functions of G762S, R938P, and G615R mutations were investigated in HEK293T cells using whole-cell patch-clamp. Homology modeling was performed to determine the locational distribution of ATP1A2 mutations.ResultsCompared with wild-type pumps, all mutations showed a similar level of protein expression and decreased cell viability in the presence of 1 µM ouabain, and there was no significant difference among the mutant groups. The changes in Na+/K+-ATPase activity were correlated with the severity of FHM phenotypes. In the presence of 100 µM ouabain, the Na+/K+-ATPase activity was FHM > FHME > FHMEI. The ouabain-sensitive Na+/K+-ATPase activity of each mutant was significantly lower than that of the wild-type protein, and there was no significant difference among all mutant groups. Whole-cell voltage-clamp recordings in HEK293T cells showed that the ouabain-sensitive pump currents of G615R were significantly reduced, while those of G762S and R938P were comparable to those of the wild-type strain.ConclusionsATP1A2 mutations cause phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability presented with severe impairment of Na+/K+-ATPase. Whether epilepsy is accompanied, or the type of epilepsy did not seem to affect the degree of impairment of pump function.
| S-EPMC8359390 | biostudies-literature
Project description:Although SCN1A, the gene encoding the neuronal voltage-gated sodium channel, type 1A, is a well-recognized target of mutations underlying a spectrum of epilepsy syndromes, and lies within an extended 12-Mb disease-associated haplotype at the familial hemiplegic migraine-3 locus, it remains to be confirmed that mutations within this gene itself cause syndromes that include migraine phenotypes. The novel T1174S missense mutation of this gene was detected segregating in a family with a heterozygous female child who presented with myoclonus and an abnormal electroencephalogram, and in her heterozygous mother, who had an ataxic migraine syndrome similar to that of her own mother. This three-generation family exhibits the broad phenotypic spectrum of the dominant neuronal hyperexcitability syndromes produced by even a given allele of this sodium channel gene. It also exhibits the second allele of this sodium channel gene associated with a migraine syndrome similar to those caused at the two other familial hemiplegic migraine loci, confirming that this gene itself, not some linked gene, is the familial hemiplegic migraine-3 locus.
| S-EPMC2151385 | biostudies-literature
Project description:Familial lecithin-cholesterol acyltransferase deficiency (FLD) is a rare recessive disorder of cholesterol metabolism, caused by loss-of-function mutations in the human LCAT gene, leading to alterations in the lipid/lipoprotein profile, with extremely low HDL levels.The classical FLD phenotype is characterized by diffuse corneal opacification, haemolytic anaemia and proteinuric chronic kidney disease (CKD); an incomplete form, only affecting the corneas, has been reported in a few families worldwide.We describe an intermediate phenotype of LCAT deficiency, with CKD preceding the development of corneal clouding, in two Portuguese brothers apparently homozygous for a novel missense LCAT gene mutation. The atypical phenotype, the diagnosis of membranous nephropathy in the proband's native kidney biopsy, the late-onset and delayed recognition of the corneal opacification, the co-segregation with Gilbert syndrome and the late recurrence of the primary disease in kidney allograft all contributed to obscure the diagnosis of an LCAT deficiency syndrome for many years.A major teaching point is that on standard light microscopy examination the kidney biopsies of patients with LCAT deficiency with residual enzyme activity may not show significant vacuolization and may be misdiagnosed as membranous nephropathy. The cases of these two patients also illustrate the importance of performing detailed physical examination in young adults presenting with proteinuric CKD, as the most important clue to the diagnosis of FLD is in the eyes.
| S-EPMC6122021 | biostudies-literature
Project description:Familial hemiplegic migraine (FHM) is an unusual migraine syndrome characterised by recurrent transient attacks of unilateral weakness or paralysis as part of the migraine aura. Genetically and clinically heterogeneous, FHM1 is caused by mutations in CACNA1A and FHM2 by mutations in ATP1A2.Three children with prolonged hemiplegia were tested for mutations in CACNA1A or ATP1A2.Mutations in CACNA1A and ATP1A2 were screened for by denaturing high performance liquid chromatography and confirmed by sequencing. Expression studies were performed to characterise the functional consequences of these mutations.No mutation was found in the FHM1 gene while three mutations were identified in the FHM2 gene. All three mutations were missense: two were novel and one was de novo; none was found in controls. Functional studies in HeLa cells showed complete loss of mutant pump function without interfering with the wild-type pump, consistent with haploinsufficiency.We identified novel disease causing mutations in the FHM2 gene. Genetic screening for FHM should be considered in a child with prolonged hemiplegia even if there is no prior history or family history of migraine or hemiplegic episodes.
| S-EPMC2117823 | biostudies-literature