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Jan B. Koenderink - One of the best experts on this subject based on the ideXlab platform.

  • biochemical characterization of sporadic familial Hemiplegic Migraine mutations
    Biochimica et Biophysica Acta, 2014
    Co-Authors: Karl M. Weigand, Herman G. P. Swarts, Frans G. M. Russel, Jan B. Koenderink
    Abstract:

    Abstract Sporadic Hemiplegic Migraine type 2 (SHM2) and familial Hemiplegic Migraine type 2 (FHM2) are rare forms of Hemiplegic Migraine caused by mutations in the Na + ,K + -ATPase α2 gene. Today, more than 70 different mutations have been linked to SHM2/FHM2, randomly dispersed over the gene. For many of these mutations, functional studies have not been performed. Here, we report the functional characterization of nine SHM2/FHM2 linked mutants that were produced in Spodoptera frugiperda (Sf)9 insect cells. We determined ouabain binding characteristics, apparent Na + and K + affinities, and maximum ATPase activity. Whereas membranes containing T345A, R834Q or R879W possessed ATPase activity significantly higher than control membranes, P796S, M829R, R834X, del 935–940 ins Ile, R937P and D999H membranes showed significant loss of ATPase activity compared to wild type enzyme. Further analysis revealed that T345A and R879W showed no changes for any of the parameters tested, whereas mutant R834Q possessed significantly decreased Na + and increased K + apparent affinities as well as decreased ATPase activity and ouabain binding. We hypothesize that the majority of the mutations studied here influence interdomain interactions by affecting formation of hydrogen bond networks or interference with the C-terminal ion pathway necessary for catalytic activity of Na + ,K + -ATPase, resulting in decreased functionality of astrocytes at the synaptic cleft expressing these mutants.

  • Familial Hemiplegic Migraine mutations affect Na,K-ATPase domain interactions.
    Biochimica et biophysica acta, 2013
    Co-Authors: Herman G. P. Swarts, Karl M. Weigand, Frans G. M. Russel, Arn M J M Van Den Maagdenberg, Hanka Venselaar, Jan B. Koenderink
    Abstract:

    Abstract Familial Hemiplegic Migraine (FHM) is a monogenic variant of Migraine with aura. One of the three known causative genes, ATP1A2, which encodes the α2 isoform of Na,K-ATPase, causes FHM type 2 (FHM2). Over 50 FHM2 mutations have been reported, but most have not been characterized functionally. Here we study the molecular mechanism of Na,K-ATPase α2 missense mutations. Mutants E700K and P786L inactivate or strongly reduce enzyme activity. Glutamic acid 700 is located in the phosphorylation (P) domain and the mutation most likely disrupts the salt bridge with Lysine 35, thereby destabilizing the interaction with the actuator (A) domain. Mutants G900R and E902K are present in the extracellular loop at the interface of the α and β subunit. Both mutants likely hamper the interaction between these subunits and thereby decrease enzyme activity. Mutants E174K, R548C and R548H reduce the Na + and increase the K + affinity. Glutamic acid 174 is present in the A domain and might form a salt bridge with Lysine 432 in the nucleotide binding (N) domain, whereas Arginine 548, which is located in the N domain, forms a salt bridge with Glutamine 219 in the A domain. In the catalytic cycle, the interactions of the A and N domains affect the K + and Na + affinities, as observed with these mutants. Functional consequences were not observed for ATP1A2 mutations found in two sporadic Hemiplegic Migraine cases (Y9N and R879Q) and in Migraine without aura (R51H and C702Y).

  • Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2
    The Journal of biological chemistry, 2008
    Co-Authors: Neslihan N. Tavraz, Tobias Freilinger, Jan B. Koenderink, Thomas Friedrich, Katharina L. Dürr, Ernst Bamberg, Martin Dichgans
    Abstract:

    Mutations in ATP1A2, the gene coding for the Na(+)/K(+)-ATPase alpha(2)-subunit, are associated with both familial Hemiplegic Migraine and sporadic cases of Hemiplegic Migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic Hemiplegic Migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na(+)/K(+)-ATPase crystal structure, a subset of the mutated residues (Ala(606), Arg(763), Met(829), and Arg(834)) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na(+)-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb(+) uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and the increased rate constants of the voltage jump-induced redistribution between E(1)P and E(2)P states were observed. Thus, mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na(+)-translocating partial reactions, corroborating the critical role of the C terminus of Na(+)/K(+)-ATPase in these processes.

R. R. Frants - One of the best experts on this subject based on the ideXlab platform.

  • cacna1a mutation linking Hemiplegic Migraine and alternating hemiplegia of childhood
    Cephalalgia, 2008
    Co-Authors: B. B. A. De Vries, Arn M J M Van Den Maagdenberg, R. R. Frants, Kaate R. J. Vanmolkot, L. A. E. M. Laan, A H Stam, Friederike Beker, I B Ginjaar, H Lauffer, Joost Haan
    Abstract:

    Familial Hemiplegic Migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.

  • two novel functional mutations in the na k atpase alpha2 subunit atp1a2 gene in patients with familial Hemiplegic Migraine and associated neurological phenotypes
    Clinical Genetics, 2007
    Co-Authors: Maria-josé Castro, Kaate R. J. Vanmolkot, B. Nunes, Carolina Lemos, J. J. M. W. Van Den Heuvel, T. Temudo, José Barros, Jorge Sequeiros, B De Vries, R. R. Frants
    Abstract:

    Mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na+,K+-ATPase, are associated with familial Hemiplegic Migraine type 2. The majority of ATP1A2 mutations were reported in patients with Hemiplegic Migraine without any additional neurological findings. Here, we report on two novel ATP1A2 mutations that were identified in two Portuguese probands with Hemiplegic Migraine and interesting additional clinical features. The proband's of family 1 (with a V362E mutation) had mood alterations, classified as a borderline personality. The proband in family 2 (with a P796S mutation) had mild mental impairment, in addition to Hemiplegic Migraine; more severe mental retardation was observed in his brother, who also had Hemiplegic Migraine and carried the same mutation. Cell-survival assays clearly showed abnormal functioning of mutant Na+,K+-ATPase, indicating that both ATP1A2 mutants are disease causing. Additionally, our results suggest a possible causal relationship of the ATP1A2 mutations with the complex clinical phenotypes observed in the probands.

  • childhood epilepsy familial Hemiplegic Migraine cerebellar ataxia and a new cacna1a mutation
    Neurology, 2004
    Co-Authors: Ee Kors, R. R. Frants, Kaate R. J. Vanmolkot, J Haan, Atle Melberg, Eva Kumlien, Raili Raininko, Roland Flink, H B Ginjaar, Maurizio Ferrari
    Abstract:

    The CACNA1A gene encodes the pore-forming subunit of neuronal P/Q type Ca2+ channels. Mutations in this gene cause a spectrum of neurologic diseases, including familial Hemiplegic Migraine (FHM) with or without ataxia.1 We report a novel de novo CACNA1A mutation in a Swedish family. Three mutation carriers had FHM and early onset ataxia; additional childhood epilepsy occurred in two . The proband, II-3, is a 54-year-old woman with slowly progressive cerebellar ataxia since childhood and cerebellar atrophy on CT. She was hospitalized at ages 7 and 8 because of decreased consciousness and vomiting for 1 day, starting with a lucid interval after a fall. She experienced four Hemiplegic Migraine attacks between ages 14 and 30 years and weekly at age 47. Seizures were never observed. Her 32-year-old son (III-5) and 30-year-old daughter (III-6), who have different fathers, showed cerebellar ataxia at age 4. Ataxia is now prominent in both, and brain imaging shows cerebellar atrophy. …

Sunseob Choi - One of the best experts on this subject based on the ideXlab platform.

Norihiro Suzuki - One of the best experts on this subject based on the ideXlab platform.

Martin Dichgans - One of the best experts on this subject based on the ideXlab platform.

  • Diverse Functional Consequences of Mutations in the Na+/K+-ATPase α2-Subunit Causing Familial Hemiplegic Migraine Type 2
    The Journal of biological chemistry, 2008
    Co-Authors: Neslihan N. Tavraz, Tobias Freilinger, Jan B. Koenderink, Thomas Friedrich, Katharina L. Dürr, Ernst Bamberg, Martin Dichgans
    Abstract:

    Mutations in ATP1A2, the gene coding for the Na(+)/K(+)-ATPase alpha(2)-subunit, are associated with both familial Hemiplegic Migraine and sporadic cases of Hemiplegic Migraine. In this study, we examined the functional properties of 11 ATP1A2 mutations associated with familial or sporadic Hemiplegic Migraine, including missense mutations (T263M, T376M, R383H, A606T, R763H, M829R, R834Q, R937P, and X1021R), a deletion mutant (del(K935-S940)ins(I)), and a frameshift mutation (S966fs). According to the Na(+)/K(+)-ATPase crystal structure, a subset of the mutated residues (Ala(606), Arg(763), Met(829), and Arg(834)) is involved in important interdomain H-bond networks, and the C terminus of the enzyme, which is elongated by the X1021R mutation, has been implicated in voltage dependence and formation of a third Na(+)-binding site. Upon heterologous expression in Xenopus oocytes, the analysis of electrogenic transport properties, Rb(+) uptake, and protein expression revealed pronounced and markedly diverse functional alterations in all ATP1A2 mutants. Abnormalities included a complete loss of function (T376M), impaired plasma membrane expression (del(K935-S940)ins(I) and S966fs), and altered apparent affinities for extracellular cations or reduced enzyme turnover (R383H, A606T, R763H, R834Q, and X1021R). In addition, changes in the voltage dependence of pump currents and the increased rate constants of the voltage jump-induced redistribution between E(1)P and E(2)P states were observed. Thus, mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences on apparent cation affinities or voltage dependence. Of interest, the X1021R mutation severely impaired voltage dependence and kinetics of Na(+)-translocating partial reactions, corroborating the critical role of the C terminus of Na(+)/K(+)-ATPase in these processes.

  • mutation in the neuronal voltage gated sodium channel scn1a in familial Hemiplegic Migraine
    The Lancet, 2005
    Co-Authors: Martin Dichgans, Michel D. Ferrari, Tobias Freilinger, Gertrud Eckstein, Elena Babini, Bettina Lorenzdepiereux, Saskia Biskup, Jurgen Herzog, Arn M J M Van Den Maagdenberg, Michael Pusch
    Abstract:

    Summary Background Familial Hemiplegic Migraine is an autosomal dominant severe subtype of Migraine with aura characterised by some degree of hemiparesis during the attacks. So far, mutations in two genes regulating ion translocation— CACNA1A and ATP1A2 —have been identified in pedigrees with this disease. Methods To identify additional genes for familial Hemiplegic Migraine, we did a genome-wide linkage analysis of two disease pedigrees without mutations in CACNA1A and ATP1A2 . Ion channel genes in the candidate interval were analysed for mutations, and the functional consequences of the recorded sequence alteration were determined. Findings We identified a novel locus for familial Hemiplegic Migraine on chromosome 2q24. Sequencing of candidate genes in this region revealed a heterozygous missense mutation (Gln1489Lys) in the neuronal voltage-gated sodium channel gene SCN1A , mutations of which have been associated with epilepsy. This same mutation was present in three families with familial Hemiplegic Migraine. It results in a charge-altering aminoacid exchange in the so-called hinged-lid domain of the protein, which is critical for fast inactivation of the channel. Whole-cell recordings in transiently transfected tsA201 cells expressing the highly homologous SCN5A sodium channel showed that the mutation induces a two-fold to four-fold accelerated recovery from fast inactivation without altering any of the other channel parameters investigated. Interpretation Dysfunction of the neuronal sodium channel SCN1A can cause familial Hemiplegic Migraine. Our findings have implications for the understanding of Migraine aura. Moreover, our study reinforces the molecular links between Migraine and epilepsy, two common paroxysmal disorders.

  • Aura in some patients with familial Hemiplegic Migraine can be stopped by intranasal ketamine.
    Neurology, 2000
    Co-Authors: Holger Kaube, Martin Dichgans, J. Herzog, T. Käufer, Hans-christoph Diener
    Abstract:

    Migraine aura is probably caused by cortical-spreading depression. No treatment for acute and severe Migraine aura has been described previously. The effect of ketamine (25 mg intranasally) was studied in 11 patients with severe, disabling auras resulting from familial Hemiplegic Migraine. In five patients ketamine reproducibly reduced the severity and duration of the neurologic deficits, whereas in the remaining six patients no beneficial effect was seen. Ketamine offers, for the first time, a possible treatment option for severe and prolonged aura.