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Biomedical subjects

Karin Jurkat-Rott

Publications and source records attributed to Karin Jurkat-Rott.

At least 19 recordsLinked to original sources
PubMed2005

3,4-Methylenedioxymethamphetamine (ecstasy) activates skeletal muscle nicotinic acetylcholine receptors.

Adverse 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) effects are usually ascribed to neurotransmitter release in the central nervous system. Since clinical features such as fasciculations, muscle cramps, rapidly progressing hyperthermia, hyperkalemia, and rhabdomyolysis point to the skeletal muscle as additional target, we studied the effects of MDMA on native and cultured skeletal muscle. We addressed the question whether malignant hyperthermia (MH)-susceptible (MHS) muscle is predisposed to adverse MDMA reactions. Force measurements on muscle strips showed that 100 microM MDMA, a concentration close to that determined in some MDMA users, regularly enhanced the sensitivity of skeletal muscle to caffeine-induced contractures but did not cause contractures on its own. The left-shift of the dose-response curve induced by MDMA was greater in normal than in MHS muscle. Furthermore, MDMA did not release Ca(2+) from isolated sarcoplasmic reticulum vesicles. These findings do not support the view of an MH-triggering effect on muscle. However, MDMA induced Ca(2+) transients in myotubes and increased their acidification rate. Surprisingly, alpha-bungarotoxin, a specific antagonist of the nicotinic acetylcholine receptor (nAChR), abolished these MDMA effects. The nAChR agonistic action of MDMA was confirmed by patch-clamp measurements of ion currents on human embryonic kidney cells expressing nAChR. We conclude that the neuromuscular junction is a target of MDMA and that an activation of nAChR contributes to the muscle-related symptoms of MDMA users. The drug may be of particular risk in individuals with abundant extrajunctional nAChR such as in generalized denervation or muscle regeneration processes and may act on central nAChR.

Animals↗
PubMed2005

Complications of anaesthesia in neuromuscular disorders.

The purpose of this review is to alert non-anaesthesiologists to the various complications from which patients with neuromuscular disorders and those susceptible to malignant hyperthermia can suffer during anaesthesia. The patient's outcome correlates with the quality of consultation between anaesthesiologists, surgeons, neurologists and cardiologists. Special precautions must be taken, since many anaesthetics and muscle relaxants can aggravate the clinical features or trigger life-threatening reactions. Complications frequently occur in these patients, although anaesthetic procedures have become safer by the reduced administration of suxamethonium and the use of total intravenous anaesthesia, new volatile anaesthetics and non-depolarising relaxants. This review provides a synopsis of pre-operative anaesthetic considerations and adverse drug effects on skeletal, cardiac and smooth muscle tissue. It describes the pathogenetic aspects of typical complications and introduces anaesthetic procedures for the various neuromuscular disorders, including regional anaesthesia for patients in whom a restriction of respiratory and/or cardiac function is predicted.

Anesthesia↗
PubMed2005

Rare missense variants in ATP1A2 in families with clustering of common forms of migraine.

Migraine is a recurrent neurovascular disease. Its two most common forms-migraine without aura (MO) and migraine with aura (MA)-both show familial clustering and a complex pattern of inheritance. Familial hemiplegic migraine (FHM) is a rare monogenic subform caused by mutations in the calcium channel gene CACNA1A or the Na(+)/K(+)-ATPase gene ATP1A2. An involvement of FHM genes in the pathogenesis of common forms of migraine is not proven. We therefore systematically screened ATP1A2 in families with several members affected by MA and/or MO. We identified two novel missense alterations [c.520G>A (p.E174 K) and c.1544G>A (p.C515Y)] in two out of 45 families, which were not found in 520 control chromosomes. Functional studies of these variants in Xenopus oocytes by two-electrode voltage clamp measurements and radiochemical determination of ATPase activity showed that C515Y leads to a complete loss of function comparable with the effect of FHM-mutations whereas for E174 K no functional alteration could be found in the in vitro assays. In conclusion we propose that rare variants in ATP1A2 are involved in the susceptibility to common forms of migraine, because of 1) the absence of alterations in controls, 2) the particular pattern of segregation in both families, 3) the high conservation of mutated residues in Na(+)/K(+)-ATPases, 4) the functional effect of C515Y, and 5) the involvement of ATP1A2 in a monogenic form of migraine.

Adult↗
PubMed2005

Preferred mexiletine block of human sodium channels with IVS4 mutations and its pH-dependence.

The effects of extracellular pH (6.2, 7.4 and 8.2) and 0.1 mM mexiletine, a channel blocker of the lidocaine type, are studied on two mutations of the fourth voltage sensor of the Nav1.4 sodium channel, R1448H/C. The fast inactivated channel state to which mexiletine preferentially binds is destabilized by the mutations. By contrast to the expected low response of R1448H/C carriers, mexiletine is particularly effective in preventing exercise-induced stiffness and paralysis from which these patients suffer. Our measurements performed in the whole-cell mode on stably transfected HEK cells show for the first time that the mutations strikingly accelerate closed-state inactivation and, as steady-state fast inactivation is shifted to more negative potentials, stabilize the fast inactivated channel state in the potential range around the resting potential. At pH 7.4 and 8.2, the phasic mexiletine block is larger for R1448C (55%) and R1448H (47%) than for wild-type channels (31%) due to slowed recovery from block (tau is approximately 520 ms for R1448C versus 270 ms for wild-type at pH 7.4) although the recovery from inactivation is slightly faster for the mutants (tau is approximately 1.9 ms for R1448C versus 3.8 ms for wild-type at pH 7.4). At pH 6.2, recovery from block is relatively fast (tau is approximately 35 ms for R1448H/C and 14 ms for wild-type) and thus shows no use-dependence. We conclude that enhanced closed-state inactivation expands the concept of a mutation-induced uncoupling of channel inactivation from activation to a new potential range and that the higher mexiletine efficacy in R1448H/C carriers compared to other myotonic patients offers a pharmacogenetic strategy for mutation-specific treatment.

Anti-Arrhythmia Agents↗
PubMed2005

Muscle channelopathies and critical points in functional and genetic studies.

Muscle channelopathies are caused by mutations in ion channel genes, by antibodies directed against ion channel proteins, or by changes of cell homeostasis leading to aberrant splicing of ion channel RNA or to disturbances of modification and localization of channel proteins. As ion channels constitute one of the only protein families that allow functional examination on the molecular level, expression studies of putative mutations have become standard in confirming that the mutations cause disease. Functional changes may not necessarily prove disease causality of a putative mutation but could be brought about by a polymorphism instead. These problems are addressed, and a more critical evaluation of the underlying genetic data is proposed.

Animals↗
PubMed2005

Ion channel defects in idiopathic epilepsies.

Idiopathic epilepsies are genetically determined diseases of the central nervous system characterized by typical epileptic seizures and EEG abnormalities but not associated with structural brain lesions. In recent years, an increasing number of mutations associated with idiopathic epilepsy syndromes were identified in genes encoding subunits of voltage- or ligand-gated ion channels. These encouraging results provide a plausible pathophysiological concept, since ion channels form the basis for neuronal excitability and are the major targets for anticonvulsive pharmacotherapy. The first epilepsy genes were identified for rare autosomal dominant syndromes within large pedigrees. Recently, a few mutations were also found for the frequent classical forms of idiopathic generalized epilepsies (IGE), for example absence or juvenile myoclonic epilepsy. The mutations can affect ion channels which on one hand have been known since several decades to be crucial for neuronal function, such as the voltage-gated sodium channel or the GABA(A) receptor, or on the other hand were newly identified within the last decade as KCNQ potassium channels or the ClC-2 chloride channel. Functional studies characterizing the molecular defects of the mutant channels point to a central role of GABAergic synaptic inhibition in the pathophysiology of IGE. Furthermore, newly discovered genes may be suitable as novel targets for pharmacotherapy such as KCNQ channels for the anticonvulsant drug retigabine. Altogether, these genetic and pathophysiological investigations will enhance our knowledge about the understanding of epileptogenesis and can help to improve anticonvulsive therapy.

Animals↗
PubMed2004

A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs.

Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with hemiparesis during the aura. In over 50% of cases the causative gene is CACNA1A (FHM1), which in some cases produces a phenotype with cerebellar signs, including ataxia and nystagmus. Recently, mutations in ATP1A2 on chromosome 1q23 encoding a Na+/K+ -ATPase subunit were identified in four families (FHM2). We now describe an FHM2 pedigree with a fifth ATP1A2 mutation coding for a G301R substitution. The phenotype was particularly severe and included hemiplegic migraine, seizure, prolonged coma, elevated temperature, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria. A mild crossed cerebellar diaschisis during an attack further supported the clinical evidence of a cerebellar deficit. This is the first report suggesting cerebellar involvement in FHM2. A possible role for CACNA1A in producing the phenotype in this family was excluded by linkage studies to the FHM1 locus. The study of this family suggests that the absence of cerebellar signs may not be a reliable indicator to clinically differentiate FHM2 from FHM1.

Adult↗
PubMed2004

Periodic paralysis mutation MiRP2-R83H in controls: Interpretations and general recommendation.

An R83H point mutation in KCNE3-encoded MiRP2 has been reported to cause 2% of all cases of familial periodic paralysis. The authors found MiRP2-R83H in 3 of 321 control subjects and in 5 unaffected related individuals. Provocation of an unaffected carrier with glucose or KCl did not induce weakness. The authors propose that causality criteria for mutations require exclusion of mutations in n = ln(P)/ln(1 - p(1)) ethnically matched control chromosomes (P = acceptable error probability; p(1) = mutation prevalence in patient chromosomes).

Aged↗
PubMed2004

Sight: automating genomic data-mining without programming skills.

SUMMARY: We created and tested Sight, a Java-based package that provides a user-friendly interface to generate and connect agents for automatic genomic data-mining for individual requirements without requiring programming skills from the user. AVAILABILITY: http://physiologie.uni-ulm.de//Seiten/Arbeitsgruppe/Jurkat-Rott/Jurkat-Rott.htm. The system does not require additional components and runs on IBM PCs under Windows (NT 4.0, 2000 and XP) or Linux (Phat 4.0 and Mandrake 9.0).

Algorithms↗
PubMed2004

Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families.

PURPOSE: Benign familial infantile convulsions (BFIC) is a form of idiopathic epilepsy. It is characterized by clusters of afebrile seizures occurring around the sixth month of life. The disease has a benign course with a normal development and rare seizures in adulthood. Previous linkage analyses defined three susceptibility loci on chromosomes 19q12-q13.11, 16p12-q12, and 2q23-31. However, a responsible gene has not been identified. We studied linkage in 16 further BFIC families. METHODS: We collected 16 BFIC families, without an additional paroxysmal movement disorder, of German, Turkish, or Japanese origin with two to eight affected individuals. Standard two-point linkage analysis was performed. RESULTS: The clinical picture included a large variety of seizure semiologies ranging from paleness and cyanosis with altered consciousness to generalized tonic-clonic seizures. Interictal EEGs showed focal epileptiform discharges in six patients, and three ictal EEGs in three distinct patients revealed a focal seizure onset in different brain regions. In all analyzed families, we found no evidence for linkage to the BFIC loci on chromosomes 19q and 2q, as well as to the known loci for benign familial neonatal convulsions on chromosomes 8q and 20q. In 14 of the families, the chromosome 16 locus could be confirmed with a cumulative maximum two-point lod score of 6.1 at marker D16S411, and the known region for BFIC could be narrowed to 22.5 Mbp between markers D16S690 and D16S3136. CONCLUSIONS: Our data confirm the importance of the chromosome 16 locus for BFIC and may narrow the relevant interval.

Adolescent↗
PubMed2003

The impact of splice isoforms on voltage-gated calcium channel alpha1 subunits.

Semi-conserved exon boundaries in members of the CACNA1 gene family result in recurring pre-mRNA splicing patterns. The resulting variations in the encoded pore-forming subunit of the voltage-gated calcium channel affect functionally significant regions, such as the vicinity of the voltage-sensing S4 segments or the intracellular loops that are important for protein interaction. In addition to generating functional diversity, RNA splicing regulates the quantitative expression of other splice isoforms of the same gene by producing transcripts with premature stop codons which encode two-domain or three-domain channels. An overview of some of the known splice isoforms of the alpha(1) calcium channel subunits and their significance is given.

Animals↗
PubMed2003

Quantification of brain atrophy in patients with myotonic dystrophy and proximal myotonic myopathy: a controlled 3-dimensional magnetic resonance imaging study.

Myotonic dystrophy (DM1) and proximal myotonic myopathy (PROMM or DM2) are two distinct muscular disorders with multisystemic involvement. Both have previously been reported to be associated with cognitive impairment and white matter lesions detected by cerebral magnetic resonance imaging (MRI). In this study, the extent of brain atrophy was investigated in vivo in ten DM1 and nine PROMM patients in comparison to age-matched healthy controls for each group. The diagnosis was confirmed by DNA analysis of all patients. As a quantitative marker, the ratio of brain parenchymal to intracranial volume, called brain parenchymal fraction (BPF), was calculated from 3-dimensional MRI data using an automated analysis technique. Compared to age-matched healthy controls (mean BPF 0.852 +/- 0.032), the BPF in DM1 patients (0.713 +/- 0.031) was highly significantly decreased (P < 0.001). In contrast, the PROMM patients (mean BPF 0.792 +/- 0.029) showed only slightly decreased BPF values (P < 0.05). BPF was not significantly correlated to any of the clinical or genetic parameters in both diseases (disease duration, motor score, educational level, and number of CTG repeats in the expanded allele). In summary, global brain atrophy was demonstrated to occur in both diseases, but was more severely manifestated in DM1 patients.

Adolescent↗
PubMed2003

Confirmation of the type 2 myotonic dystrophy (CCTG)n expansion mutation in patients with proximal myotonic myopathy/proximal myotonic dystrophy of different European origins: a single shared haplotype indicates an ancestral founder effect.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, is a clinically and genetically heterogeneous neuromuscular disorder. DM is characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multisystem involvement. Type 1 DM (DM1) is caused by a (CTG)(n) expansion in the 3' untranslated region of DMPK in 19q13.3. Multiple families, predominantly of German descent and with clinically variable presentation that included proximal myotonic myopathy (PROMM) and type 2 DM (DM2) but without the DM1 mutation, showed linkage to the 3q21 region and were recently shown to segregate a (CCTG)(n) expansion mutation in intron 1 of ZNF9. Here, we present linkage to 3q21 and mutational confirmation in 17 kindreds of European origin with PROMM and proximal myotonic dystrophy, from geographically distinct populations. All patients have the DM2 (CCTG)(n) expansion. To study the evolution of this mutation, we constructed a comprehensive physical map of the DM2 region around ZNF9. High-resolution haplotype analysis of disease chromosomes with five microsatellite and 22 single-nucleotide polymorphism markers around the DM2 mutation identified extensive linkage disequilibrium and a single shared haplotype of at least 132 kb among patients from the different populations. With the exception of the (CCTG)(n) expansion, the available markers indicate that the DM2 haplotype is identical to the most common haplotype in normal individuals. This situation is reminiscent of that seen in DM1. Taken together, these data suggest a single founding mutation in DM2 patients of European origin. We estimate the age of the founding haplotype and of the DM2 (CCTG) expansion mutation to be approximately 200-540 generations.

Base Sequence↗
PubMed2003

Impaired slow inactivation due to a polymorphism and substitutions of Ser-906 in the II-III loop of the human Nav1.4 channel.

The loop connecting domains II and III of the sodium channel alpha-subunit is not known to have a major effect on channel gating. Recently mutations in the II-III loop of various sodium channel isoforms have been reported to cause channelopathies suggesting the functional importance of this region. In the II-III loop of the skeletal muscle isoform Na(v)1.4, we found a Ser-to-Thr substitution at position 906 in 5% of patients with dyskalemic periodic paralysis but also in 4% of healthy human individuals. To investigate whether this position is important for channel gating, we characterized the following amino acids at 906 by whole-cell patch-clamp experiments: Gln, Ser, Thr, Cys, Pro, Val, ordered according to their hydrophobicity. All substitutions mainly affected slow inactivation. For example, Gln caused a +13-mV right-shift of the steady-state slow inactivation curve, and entry into slow inactivation was 6 times slower compared with Ser, leading to a destabilization of the slow inactivated state; in contrast, Val, at the other end of the hydrophobicity spectrum, shifted the steady-state slow inactivation curve by -6 mV and slowed the recovery from the slow inactivated state threefold compared with Ser, resulting in an enhancement of slow inactivation. Recovery from the slow inactivated state was also slowed by Pro, Cys and Thr. Our results suggest that (1) a benign polymorphism affects channel function, (2) the II-III loop is important for slow inactivation, and (3) the effects on slow inactivation may depend on the hydrophobicity of the residue at position 906.

Amino Acid Substitution↗
PubMed2002

Several interacting genes influence the malignant hyperthermia phenotype.

Malignant hyperthermia (MH), a potentially lethal disorder of skeletal muscle calcium homeostasis, manifests only on exposure to certain anaesthetic drugs. The mode of inheritance appears to be autosomal dominant with both locus and allelic heterogeneity having been reported. Association analysis of eight MH candidate loci in UK families has indicated that several genes influence susceptibility in individual families, rather than MH simply being a major gene defect. In support of this hypothesis, we present data on a replica analysis of an independent sample of European MH families.

Calcium Channels, L-Type↗
PubMed2002

Skeletal muscle channelopathies.

Ion channelopathies have common clinical features, recurrent patterns of mutations, and almost predictable mechanisms of pathogenesis. In skeletal muscle, disorders are associated with mutations in voltage-gated Na(+), K(+), Ca(2+), and Cl(-) channels leading to hypoexcitability, causing periodic paralysis and to hyperexcitabilty, resulting in myotonia or susceptibility to malignant hyperthermia.

Humans↗