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5. Muscle dysfunction caused by a [K.sub.ATP] channel mutation in neonatal diabetes is neuronal in origin

Author

Clark, Rebecca H., McTaggart, James S., Webster, Richard, Mannikko, Roope, Iberl, Michaela, Sim, Xiu Li, Rorsman, Patrik, Glitsch, Maike, Beeson, David, and Ashcroft, Frances M.

Subjects
Neurons -- Health aspects, Diabetes -- Development and progression, Muscle diseases -- Causes of, Potassium channels -- Health aspects, Infants (Newborn) -- Diseases, Infants (Newborn) -- Development and progression, Science and technology
Abstract

Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)--sensitive potassium ([K.sub.ATP]) channel, cause neonatal diabetes. Many patients also suffer from hypotonia (weak and flaccid muscles) and balance problems. The diabetes arises from suppressed insulin secretion by overactive [K.sub.ATP] channels in pancreatic [beta]-cells, but the source of the motor phenotype is unknown. By using mice carrying a human Kir6.2 mutation ([Val.sup.59] [right arrow] [Met.sup.59]) targeted to either muscle or nerve, we show that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. We also identify locomotor hyperactivity as a feature of [K.sub.ATP] channel overactivity. These findings suggest that drugs targeted against neuronal, rather than muscle, [K.sub.ATP] channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability. 10.1126/science.1186146

Published
2010
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8. Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties

Author

Mannikko, Roope, Pandey, Shilpi, Larsson, H. Peter, and Elinder, Fredrik

Subjects
Pacemaker, Artificial (Heart), Nucleotides, Arrhythmia, Cardiovascular equipment, Biological sciences, Health
Abstract

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are important for rhythmic activity in the brain and in the heart. In this study, using ionic and gating current measurements, we show that cloned spHCN channels undergo a hysteresis in their voltage dependence during normal gating. For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential. In addition, the kinetics of the tail current and the activation current change in parallel to the voltage shifts of the Q(V) and G(V) curves. Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis. We propose a model in which HCN channels transit between two modes. The voltage dependence in the two modes is shifted relative to each other, and the occupancy of the two modes depends on the previous activation of the channel. The shifts in the voltage dependence are fast ([tau] [approximately equal to] 100 ms) and are not accompanied by any apparent inactivation. In HCN1 channels, the shift in voltage dependence is slower in a 100 mM K extracellular solution compared with a 1 mM K solution. Based on these findings, we suggest that molecular conformations similar to slow (C-type) inactivation of K channels underlie voltage hysteresis in HCN channels. The voltage hysteresis results in HCN channels displaying different voltage dependences during different phases in the pacemaker cycle. Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells. KEY WORDS: HCN channel * voltage shift * voltage clamp * oocyte * arrhythmia

Published
2005

9. Molecular movement of the voltage sensor in a K channel

Author

Broomand, Amir, Mannikko, Roope, Larsson, H. Peter, and Elinder, Fredrik

Subjects
Physiology -- Research, Biological sciences, Health
Abstract

The X-ray crystallographic structure of KvAP, a voltage-gated bacterial K channel, was recently published. However, the position and the molecular movement of the voltage sensor, S4, are still controversial. For example, in the crystallographic structure, S4 is located far away (>30 [Angstrom]) from the pore domain, whereas electrostatic experiments have suggested that S4 is located close ( KEY WORDS: Shaker K channel * voltage gated * disulfide * S4 movement * helical screw

Published
2003

10. Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages

Author

Mannikko, Roope, Elinder, Fredrik, and Larsson, H. Peter

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Roope Männikkö [1]; Fredrik Elinder [1]; H. Peter Larsson (corresponding author) [2] Hyperpolarization-activated cyclic-nucleotide-gated (HCN) ion channels are found in rhythmically firing cells in the brain and in the [...]

Published
2002
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11. Mutations of the same conserved glutamate residue in NBD2 of the sulfonylurea receptor 1 subunit of the [K.sub.ATP] channel can result in either hyperinsulinism or neonatal diabetes

Author

Mannikko, Roope, Flanagan, Sarah E., Sim, Xiuli, Segal, David, Hussain, Khalid, Ellard, Sian, Hattersley, Andrew T., and Ashcroft, Frances M.

Subjects
Gene mutations -- Physiological aspects -- Research, Potassium channels -- Physiological aspects -- Genetic aspects -- Research, Diabetes in children -- Risk factors -- Genetic aspects -- Research, Health
Abstract

OBJECTIVE--Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K+ channel ([K.sub.ATP] channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygously in patients with neonatal diabetes. A mutation at the same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. We sought to understand why mutations at the same residue can cause either neonatal diabetes or hyperinsulinemia. RESEARCH DESIGN AND METHODS--Neonatal diabetic patients were sequenced for mutations in ABCC8 (SUR1) and KCNJ11 (Kir6.2). Wild-type and mutant [K.sub.ATP] channels were expressed in Xenopus laevis oocytes and studied with electrophysiological methods. RESULTS--Oocytes expressing neonatal diabetes mutant channels had larger resting whole-cell [K.sub.ATP] currents than wild-type, consistent with the patients' diabetes. Conversely, no E1506K currents were recorded at rest or after metabolic inhibition, as expected for a mutation causing hyperinsulinemia. [K.sub.ATP] channels are activated by Mg-nucleotides (via SUR1) and blocked by ATP (via Kir6.2). All mutations decreased channel activation by MgADP but had little effect on MgATP activation, as assessed using an ATP-insensitive Kir6.2 subtmit. Importantly, using wild-type Kir6.2, a 30-s preconditioning exposure to physiological MgATP concentrations (>300 µmol/L) caused a marked reduction in the ATP sensitivity of neonatal diabetic channels, a small decrease in that of wild-type channels, and no change for E1506K channels. This difference in MgATP inhibition may explain the difference in resting whole-cell currents found for the neonatal diabetes and hyperinsulinemia mutations. CONCLUSIONS--Mutations in the same residue can cause either hyperinsulinemia or neonatal diabetes. Differentially altered nucleotide regulation by NBD2 of SUR1 can explain the respective clinical phenotypes. Diabetes 60:1813-1822, 2011, The ATP-sensitive [K.sup.+] ([K.sub.ATP]) channel plays a central role in glucose-stimulated insulin secretion from the pancreatic β-cell by linking the metabolic state of the cell to its electrical excitability (1-3). [...]

Published
2011
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12. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, Tucci Arianna, Salpietro Vincenzo, Dixon Christine L., Guo Hui, Bello Oscar D., Vandrovcova Jana, Efthymiou Stephanie, Maroofian Reza, Heimer Gali, Burglen Lydie, Valence Stephanie, Torti Erin, Hacke Moritz, Rankin Julia, Tariq Huma, Colin Estelle, Procaccio Vincent, Striano Pasquale, Mankad Kshitij, Lieb Andreas, Chen Sharon, Pisani Laura, Bettencourt Conceicao, Mannikko Roope, Manole Andreea, Brusco Alfredo, Grosso Enrico, Ferrero Giovanni Battista, Armstrong-Moron Judith, Gueden Sophie, Bar-Yosef Omer, Tzadok Michal, Monaghan Kristin G., Santiago-Sim Teresa, Person Richard E., Cho Megan T., Willaert Rebecca, Yoo Yongjin, Chae Jong-Hee, Quan Yingting, Wu Huidan, Wang Tianyun, Bernier Raphael A., Xia Kun, Blesson Alyssa, Jain Mahim, Motazacker Mohammad M., Jaeger Bregje, Schneider Amy L., Boysen Katja, Muir Alison M., Myers Candace T., Gavrilova Ralitza H., Gunderson Lauren, Schultz-Rogers Laura, Klee Eric W., Dyment David, Osmond Matthew, Parellada Mara, Llorente Cloe, Gonzalez-Penas Javier, Carracedo Angel, Van Haeringen Arie, Ruivenkamp Claudia, Nava Caroline, Heron Delphine, Nardello Rosaria, Iacomino Michele, Minetti Carlo, Skabar Aldo, Fabretto Antonella, Chez Michael, Tsai Anne, Fassi Emily, Shinawi Marwan, Constantino John N., De Zorzi Rita, Fortuna Sara, Kok Fernando, Keren Boris, Bonneau Dominique, Choi Murim, Benzeev Bruria, Zara Federico, Mefford Heather C., Scheffer Ingrid E., Clayton-Smith Jill, Macaya Alfons, Rothman James E., Eichler Evan E., Kullmann Dimitri M., Houlden Henry, Raspall-Chaure Miquel, Hanna Michael G., Bugiardini Enrico, Hostettler Isabel, O'Callaghan Benjamin, Khan Alaa, Cortese Andrea, O'Connor Emer, Yau Wai Y., Bourinaris Thomas, Kaiyrzhanov Rauan, Chelban Viorica, Madej Monika, Diana Maria C., Vari Maria S., Pedemonte Marina, Bruno Claudio, Balagura Ganna, Scala Marcello, Fiorillo Chiara, Nobili Lino, Malintan Nancy T., Zanetti Maria N., Krishnakumar Shyam S., Lignani Gabriele, Jepson James E. C., Broda Paolo, Baldassari Simona, Rossi Pia, Fruscione Floriana, Madia Francesca, Traverso Monica, De-Marco Patrizia, Perez-Duenas Belen, Munell Francina, Kriouile Yamna, El-Khorassani Mohamed, Karashova Blagovesta, Avdjieva Daniela, Kathom Hadil, Tincheva Radka, Van-Maldergem Lionel, Nachbauer Wolfgang, Boesch Sylvia, Gagliano Antonella, Amadori Elisabetta, Goraya Jatinder S., Sultan Tipu, Kirmani Salman, Ibrahim Shahnaz, Jan Farida, Mine, Jun, Banu Selina, Veggiotti Pierangelo, Zuccotti Gian V, Ferrari Michel D., Van Den Maagdenberg Arn M. J., Verrotti Alberto, Marseglia Gian L., Savasta Salvatore, Soler Miguel A., Scuderi Carmela, Borgione Eugenia, Chimenz Roberto, Gitto Eloisa, Dipasquale Valeria, Sallemi Alessia, Fusco Monica, Cuppari Caterina, Cutrupi Maria C., Ruggieri Martino, Cama Armando, Capra Valeria, Mencacci Niccolo E., Boles Richard, Gupta Neerja, Kabra Madhulika, Papacostas Savvas, Zamba-Papanicolaou Eleni, Dardiotis Efthymios, Maqbool Shazia, Rana Nuzhat, Atawneh Osama, Lim Shen Y., Shaikh Farooq, Koutsis George, Breza Marianthi, Coviello Domenico A., Dauvilliers Yves A., AlKhawaja Issam, AlKhawaja Mariam, Al-Mutairi Fuad, Stojkovic Tanya, Ferrucci Veronica, Zollo Massimo, Alkuraya Fowzan S., Kinali Maria, Sherifa Hamed, Benrhouma Hanene, Turki Ilhem B. Y., Tazir Meriem, Obeid Makram, Bakhtadze Sophia, Saadi Nebal W., Zaki Maha S., Triki Chahnez C., Benfenati Fabio, Gustincich Stefano, Kara Majdi, Belcastro Vincenzo, Specchio Nicola, Capovilla Giuseppe, Karimiani Ehsan G., Salih Ahmed M., Okubadejo Njideka U., Ojo Oluwadamilola O., Oshinaike Olajumoke O., Oguntunde Olapeju, Wahab Kolawole, Bello Abiodun H., Abubakar Sanni, Obiabo Yahaya, Nwazor Ernest, Ekenze Oluchi, Williams Uduak, Iyagba Alagoma, Taiwo Lolade, Komolafe Morenikeji, Senkevich Konstantin, Shashkin Chingiz, Zharkynbekova Nazira, Koneyev Kairgali, Manizha Ganieva, Isrofilov Maksud, Guliyeva Ulviyya, Salayev Kamran, Khachatryan Samson, Rossi Salvatore, Silvestri Gabriella, Haridy Nourelhoda, Ramenghi Luca A., Xiromerisiou Georgia, David Emanuele, Aguennouz Mhammed, Fidani Liana, Spanaki Cleanthe, and Tucci Arianna

Published
2019

14. WED 236 Skeletal muscle channelopathies and sudden infant death syndrome

Author

Wong Leonie, Matthews Emma, Mannikko Roope, Behr Elijah, Fleming Peter, Kullmann Dimitri, Sisodiya Sanjay, and Hanna Michael

Subjects
Pregnancy, business.industry, Skeletal muscle, Periodic paralysis, Sudden infant death syndrome, medicine.disease, Myotonia, Bioinformatics, Psychiatry and Mental health, medicine.anatomical_structure, Channelopathy, Respiratory muscle, Medicine, Surgery, Neurology (clinical), Laryngospasm, medicine.symptom, business
Abstract

BackgroundSkeletal muscle channelopathies are rare genetic disorders causing periodic paralysis and myotonia. They are generally considered debilitating but not life-threatening. However cases of life-threatening respiratory muscle crises have recently been reported in infants requiring ITU support. We hypothesised muscle channelopathy gene variants may contribute to the risk of sudden infant death.MethodsWe analysed the SCN4A gene for rare variants in 278 cases of sudden infant death (SIDS) and 729 ethnically matched controls. Biophysical characterisation was performed using a heterologous expression system.ResultsFour of the 278 SIDS cases (1.4%) had an ultra-rare, functionally disruptive SCN4A variant compared to 0/729 ethnically matched controls (p=0.0057). The degree of channel perturbation associated with these four variants was qualitatively similar to the SCN4A variants previously implicated in infants with life-threatening apnoeic events.ConclusionsRare SCN4A variants that directly alter channel function occur in sudden infant death cases. These variants are predicted to significantly alter muscle membrane excitability compromising respiratory and laryngeal function. Data on pregnancy/post-natal complications is now being collected from parents with genetically confirmed sodium channelopathies via clinic and on-line registry. Laryngospasm has recently been implicated in SUDEP - analysis of SCN4A variants in SUDEP cases is also underway.

Published
2018

15. S4 Charges Move Close to Residues in the Pore Domain during Activation in a K Channel

Author

ELINDER, FREDRIK, MANNIKKO, ROOPE, and LARSSON, H. PETER

Subjects
Potassium channels -- Physiological aspects, Voltage-clamp technique (Electrophysiology) -- Research, Electrophysiology -- Research, Biological sciences, Health
Abstract

Voltage-gated ion channels respond to changes in the transmembrane voltage by opening or closing their ion conducting pore. The positively charged fourth transmembrane segment (S4) has been identified as the main voltage sensor, but the mechanisms of coupling between the voltage sensor and the gates are still unknown. Obtaining information about the location and the exact motion of S4 is an important step toward an understanding of these coupling mechanisms. In previous studies we have shown that the extracellular end of S4 is located close to segment 5 (S5). The purpose of the present study is to estimate the location of S4 charges in both resting and activated states. We measured the modification rates by differently charged methanethiosulfonate regents of two residues in the extracellular end of S5 in the Shaker K channel (418C and 419C). When S4 moves to its activated state, the modification rate by the negatively charged sodium (2-sulfonatoethyl) methanethiosulfonate ([MTSES.sup.-]) increases significantly more than the modification rate by the positively charged [2-(trimethylammonium)ethyl] methanethiosulfonate, bromide ([MTSET.sup.+]). This indicates that the positive S4 charges are moving close to 418C and 419C in S5 during activation. Neutralization of the most external charge of S4 (R362), shows that R362 in its activated state electrostatically affects the environment at 418C by 19 mV. In contrast, R362 in its resting state has no effect on 418C. This suggests that, during activation of the channel, R362 moves from a position far away ([is greater than] 20 [Angstrom]) to a position close (8 [Angstrom]) to 418C. Despite its close approach to E418, a residue shown to be important in slow inactivation, R362 has no effect on slow inactivation or the recovery from slow inactivation. This refutes previous models for slow inactivation with an electrostatic S4-to-gate coupling. Instead, we propose a model with an allosteric mechanism for the S4-to-gate coupling. KEY WORDS: electrostatics * cysteine reactivity * Shaker * voltage clamp * Xenopus oocytes

Published
2001

17. Possible role of SCN4A skeletal muscle mutation in apnea during seizure

Author

Michael G. Hanna, Kayihan Uluc, Roope Männikkö, Sanjay M. Sisodiya, Asli Gundogdu, Dilsad Turkdogan, Hande Caglayan, Sunay Usluer, Emma Matthews, Turkdogan, Dilsad, Matthews, Emma, Usluer, Sunay, Gundogdu, Asli, Uluc, Kayihan, Mannikko, Roope, Hanna, Michael G., Sisodiya, Sanjay M., and Caglayan, Hande S.

Subjects
SUDEP, Myotonic Disorder, Gene mutation, medicine.disease_cause, Bioinformatics, lcsh:RC346-429, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, 030225 pediatrics, medicine, Short Research Article, Laryngospasm, lcsh:Neurology. Diseases of the nervous system, Mutation, laryngospasm, business.industry, Apnea, Sudden infant death syndrome, medicine.disease, Myotonia, myotonia, Neurology, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, sodium channel
Abstract

SCN4A gene mutations cause a number of neuromuscular phenotypes including myotonia. A subset of infants with myotonia‐causing mutations experience severe life‐threatening episodic laryngospasm with apnea. We have recently identified similar SCN4A mutations in association with sudden infant death syndrome. Laryngospasm has also been proposed as a contributory mechanism to some cases of sudden unexpected death in epilepsy (SUDEP). We report an infant with EEG‐confirmed seizures and recurrent apneas. Whole‐exome sequencing identified a known pathogenic mutation in the SCN4A gene that has been reported in several unrelated families with myotonic disorder. We propose that the SCN4A mutation contributed to the apneas in our case, irrespective of the underlying cause of the epilepsy. We suggest this supports the notion that laryngospasm may contribute to some cases of SUDEP, and implicates a possible shared mechanism between a proportion of sudden infant deaths and sudden unexpected deaths in epilepsy.

Published
2019

18. Muscle Dysfunction Caused by a KATP Channel Mutation in Neonatal Diabetes Is Neuronal in Origin.

Author

Clark, Rebecca H., McTaggart, James S., Webster, Richard, Mannikko, Roope, Iberl, Michaela, Xiu Li Sim, Rorsman, Patrik, Glitsch, Maike, Beeson, David, and Ashcroft, Frances M.

Subjects
*POTASSIUM channels, *GENETIC mutation, *ADENOSINE triphosphate, *MUSCLE hypotonia, *INFANT diseases, *GENETICS of diabetes, *ANIMAL models of diabetes
Abstract

Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel, cause neonatal diabetes. Many patients also suffer from hypotonia (weak and flaccid muscles) and balance problems. The diabetes arises from suppressed insulin secretion by overactive KATP channels in pancreatic β-cells, but the source of the motor phenotype is unknown. By using mice carrying a human Kir6.2 mutation (Val59 → Met59) targeted to either muscle or nerve, we show that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. We also identify locomotor hyperactivity as a feature of KATP channel overactivity. These findings suggest that drugs targeted against neuronal, rather than muscle, KATP channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability. [ABSTRACT FROM AUTHOR]

Published
2010
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