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A missense mutation...
A missense mutation converts the Na+,K+-ATPase into an ion channel and causes therapy-resistant epilepsy.
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- Ygberg, Sofia (author)
- Karolinska Institutet
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- Akkuratov, Evgeny E. (author)
- KTH,Biofysik,Science for Life Laboratory, SciLifeLab,Department of Applied Physics, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden
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- Howard, Rebecca J. (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab),Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden
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- Taylan, Fulya (author)
- Karolinska Institutet
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- Jans, Daniel C. (author)
- KTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,Department of Applied Physics, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden
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- Mahato, Dhani R. (author)
- Umeå universitet,Kemiska institutionen
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- Katz, Adriana (author)
- Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel.,Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovoth, Israel
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- Kinoshita, Paula F (author)
- Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo, Brazil.,Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
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- Portal, Benjamin (author)
- Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.,Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
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- Nennesmo, Inger (author)
- Karolinska Institutet
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- Lindskog, Maria (author)
- Karolinska Institutet
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- Karlish, Steven J D (author)
- Weizmann Inst Sci, Dept Biomol Sci, Rehovot, Israel.,Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovoth, Israel
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- Andersson, Magnus (author)
- Umeå universitet,Kemiska institutionen
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- Lindstrand, Anna (author)
- Karolinska Institutet
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- Brismar, Hjalmar (author)
- Karolinska Institutet,KTH,Biofysik,Science for Life Laboratory, SciLifeLab,Karolinska Inst, Sci Life Lab, Dept Womens & Childrens Hlth, Stockholm, Sweden.,Department of Applied Physics, Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden; Department of Women's and Children's Health, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
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- Aperia, Anita (author)
- Karolinska Institutet
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(creator_code:org_t)
- Elsevier, 2021
- 2021
- English.
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In: Journal of Biological Chemistry. - : Elsevier. - 0021-9258 .- 1083-351X. ; 297:6
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Abstract
Subject headings
Close
- The ion pump Na+,K+-ATPase is a critical determinant of neuronal excitability; however, its role in the etiology of diseases of the central nervous system (CNS) is largely unknown. We describe here the molecular phenotype of a Trp931Arg mutation of the Na+,K+-ATPase catalytic α1 subunit in an infant diagnosed with therapy-resistant lethal epilepsy. In addition to the pathological CNS phenotype, we also detected renal wasting of Mg2+. We found that membrane expression of the mutant α1 protein was low, and ion pumping activity was lost. Arginine insertion into membrane proteins can generate water-filled pores in the plasma membrane, and our molecular dynamic (MD) simulations of the principle states of Na+,K+-ATPase transport demonstrated massive water inflow into mutant α1 and destabilization of the ion-binding sites. MD simulations also indicated that a water pathway was created between the mutant arginine residue and the cytoplasm, and analysis of oocytes expressing mutant α1 detected a nonspecific cation current. Finally, neurons expressing mutant α1 were observed to be depolarized compared with neurons expressing wild-type protein, compatible with a lowered threshold for epileptic seizures. The results imply that Na+,K+-ATPase should be considered a neuronal locus minoris resistentia in diseases associated with epilepsy and with loss of plasma membrane integrity.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- Na
- K-ATPase
- arginine mutation
- de novo mutation
- epilepsy
- leak channel
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Ygberg, Sofia
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Akkuratov, Evgen ...
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Howard, Rebecca ...
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Taylan, Fulya
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Jans, Daniel C.
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Mahato, Dhani R.
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show more...
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Katz, Adriana
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Kinoshita, Paula ...
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Portal, Benjamin
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Nennesmo, Inger
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Lindskog, Maria
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Karlish, Steven ...
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Andersson, Magnu ...
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Lindstrand, Anna
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Brismar, Hjalmar
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Aperia, Anita
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
- Articles in the publication
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Journal of Biolo ...
- By the university
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Uppsala University
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Royal Institute of Technology
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Stockholm University
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Umeå University
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Karolinska Institutet