Genetics, Gene Therapy & Genetic Disease
- Sodium permeable and “hypersensitive” TREK‐1 channels cause ventricular tachycardia
- Niels Decher (decher{at}staff.uni-marburg.de)*,1,†,
- Beatriz Ortiz‐Bonnin1,†,
- Corinna Friedrich3,
- Marcus Schewe4,
- Aytug K Kiper1,
- Susanne Rinné1,
- Gunnar Seemann5,6,
- Rémi Peyronnet5,6,
- Sven Zumhagen3,
- Daniel Bustos7,
- Jens Kockskämper2,
- Peter Kohl5,6,
- Steffen Just8,
- Wendy González7,
- Thomas Baukrowitz4,
- Birgit Stallmeyer3 and
- Eric Schulze‐Bahr3
- 1Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps‐University of Marburg, Marburg, Germany
- 2Institute of Pharmacology and Clinical Pharmacy, Biochemical and Pharmacological Center (BPC) Philipps‐University of Marburg, Marburg, Germany
- 3Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany
- 4Institute of Physiology, Christian‐Albrechts‐University of Kiel, Kiel, Germany
- 5Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg – Bad Krozingen, Medical Center – University of Freiburg, Freiburg, Germany
- 6Faculty of Medicine, University of Freiburg, Freiburg, Germany
- 7Center for Bioinformatics and Molecular Simulation, University of Talca, Talca, Chile
- 8Molecular Cardiology, University Hospital Ulm, Ulm, Germany
- ↵*Corresponding author. Tel: +49 6421 2862148; E‐mail: decher{at}staff.uni-marburg.de
↵† These authors contributed equally to this work
A point mutation in the selectivity filter of the stretch‐activated K2P potassium channel TREK‐1 was identified in a patient with right ventricular outflow tract tachycardia. The mutation most likely causes arrhythmias through abnormal sodium permeability and hypersensitivity to stretch‐activation.
Synopsis
A point mutation in the selectivity filter of the stretch‐activated K2P potassium channel TREK‐1 was identified in a patient with right ventricular outflow tract tachycardia. The mutation most likely causes arrhythmias through abnormal sodium permeability and hypersensitivity to stretch‐activation.
Analysis of a patient with right ventricular outflow tract tachycardia (RVOT‐VT) led to the identification of a heterozygous mutation, resulting in an Ile to Thr exchange directly preceding the selectivity filter of the K2P potassium channel TREK‐1.
The mutation introduces an abnormal sodium permeability and a hypersensitivity to stretch‐activation to TREK‐1 channels.
The study suggests that the selectivity filter is directly involved in stretch‐induced activation and desensitization of stretch‐sensitive K2P potassium channels.
Increased sodium permeability and stretch‐sensitivity of mutant TREK‐1 channels may trigger arrhythmias in areas of the heart with high physical strain.
The findings provide important insights for future studies of K2P channel stretch‐activation and the role of TREK‐1 in mechano‐electrical feedback in the heart.
EMBO Mol Med (2017) 9: 403–414
- Received June 9, 2016.
- Revision received January 19, 2017.
- Accepted January 23, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias
- Shiraz Haron‐Khun1,2,†,
- David Weisbrod1,†,
- Hanna Bueno1,†,
- Dor Yadin2,†,
- Joachim Behar3,
- Asher Peretz1,
- Ofer Binah4,
- Edith Hochhauser5,
- Michael Eldar2,
- Yael Yaniv3,
- Michael Arad (michael.arad{at}sheba.health.gov.il)*,2 and
- Bernard Attali (battali{at}post.tau.ac.il)*,1
- 1Department of Physiology and Pharmacology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- 2Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Tel Aviv, Israel
- 3Laboratory of Bioenergetic and Bioelectric Systems, Biomedical Engineering Faculty, Technion—Israel Institute of Technology, Haifa, Israel
- 4Department of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa, Israel
- 5The Cardiac Research Laboratory of the Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel
- ↵*
Corresponding author. Tel: +972 3 5304560; E‐mail: michael.arad{at}sheba.health.gov.il
Corresponding author. Tel: +972 3 6405116; E‐mail: battali{at}post.tau.ac.il
↵† These authors contributed equally to this work
SK4 Ca2+‐activated K+ channels are important for embryonic cardiac pacemaker function, and are now found to be crucial for adult sinoatrial node (SAN) pacing and successfully targeted for treatment of cardiac arrhythmias in mice.
Synopsis
SK4 Ca2+‐activated K+ channels are important for embryonic cardiac pacemaker function, and are now found to be crucial for adult sinoatrial node (SAN) pacing and successfully targeted for treatment of cardiac arrhythmias in mice.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited stress‐provoked ventricular arrhythmia, which also manifests sinoatrial node dysfunction.
SK4 channels are identified in hiPSC cardiomyocytes (CMs) from healthy and CPVT2 patients and in SAN cells from WT and CASQ2‐D307H knock‐in (KI) mice.
The SK4 channel blocker TRAM‐34 reduces the arrhythmic Ca2+ transients observed in CPVT2‐derived hiPSC‐CMs and in SAN cells from KI mice.
TRAM‐34 prominently decreased the ECG arrhythmic features of CASQ2‐D307H KI and CASQ2 knockout mice.
SK4 channels are promising therapeutic targets for the treatment of cardiac arrhythmias such as CPVT.
EMBO Mol Med (2017) 9: 415–429
- Received August 8, 2016.
- Revision received January 23, 2017.
- Accepted January 25, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Patient‐driven search for rare disease therapies: the Fondazione Telethon success story and the strategy leading to Strimvelis
- Lucia Monaco (lmonaco{at}telethon.it)@Telethonitalia1 and
- Lucia Faccio1
The recent approval of Strimvelis, the first ex vivo gene therapy to gain marketing authorization (Schimmer & Breazzano, 2016), has drawn attention to Fondazione Telethon, the Italian charity that played a pivotal role in this effort. Although it is not uncommon that advanced therapies, such as Strimvelis, are developed by partnerships between academia and industry, direct involvement of a charity in key steps of this process is still unusual. Illustrating the strategies and operational model adopted by Fondazione Telethon to achieve its mission of supporting excellent research aimed at curing rare genetic diseases may elucidate some of the enabling factors behind the Strimvelis success story.
The successful Italian Fondazione Telethon model. A charity supporting excellence in rare genetic disease research from basic to translational and clinical development, including engagement with the pharmaceutical industry and regulatory agencies.
- © 2017 Fondazione Telethon Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Modulation of mTOR signaling as a strategy for the treatment of Pompe disease
- Jeong‐A Lim1,2,†,‡,
- Lishu Li (lishuli1{at}hotmail.com)*,1,†,‡,
- Orian S Shirihai3,
- Kyle M Trudeau3,
- Rosa Puertollano (puertolr{at}mail.nih.gov)*,2,‡ and
- Nina Raben (rabenn{at}mail.nih.gov)*,1,‡
- 1Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
- 2Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
- 3Department of Medicine, Obesity and Nutrition Section, Evans Biomedical Research Center, Boston University School of Medicine, Boston, MA, USA
- ↵*
Corresponding author. E‐mail: lishuli1{at}hotmail.com
Corresponding author. Tel: +1 301 451 2361; E‐mail: puertolr{at}mail.nih.gov
Corresponding author. Tel: +1 301 496 1474; E‐mail: rabenn{at}mail.nih.gov
↵† These authors contributed equally to this work
Muscle loss is a feature of lysosomal glycogen storage disorder Pompe disease, also known as acid maltase deficiency. mTORC1 is a key regulator of protein synthesis in muscle. Myotubes and whole muscle from Pompe mice display aberrant mTOR signaling.
Synopsis
Muscle loss is a feature of lysosomal glycogen storage disorder Pompe disease, also known as acid maltase deficiency. mTORC1 is a key regulator of protein synthesis in muscle. Myotubes and whole muscle from Pompe mice display aberrant mTOR signaling.
mTOR activity is diminished in the diseased muscle cells.
mTOR is not fully inactivated in the diseased cells after starvation.
mTOR remains at the lysosome irrespective of nutrient availability.
Lysosomal acidification defect and activation of the AMPK‐tuberous sclerosis complex (TSC) pathway are the major culprits responsible for the defective mTOR signaling.
TSC inhibition and l‐arginine treatments largely correct the defects.
EMBO Mol Med (2017) 9: 353–370
- Received April 26, 2016.
- Revision received December 14, 2016.
- Accepted December 16, 2016.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome
- Tzipora C Falik‐Zaccai (falikmd.genetics{at}gmail.com)*,1,2,
- Yiftah Barsheshet2,†,
- Hanna Mandel3,4,†,
- Meital Segev2,
- Avraham Lorber4,5,
- Shachaf Gelberg2,
- Limor Kalfon1,
- Shani Ben Haroush1,
- Adel Shalata6,
- Liat Gelernter‐Yaniv7,
- Sarah Chaim1,
- Dorith Raviv Shay1,
- Morad Khayat8,
- Michal Werbner2,
- Inbar Levi1,
- Yishay Shoval1,
- Galit Tal3,4,
- Stavit Shalev4,8,
- Eli Reuveni2,
- Emily Avitan‐Hersh9,
- Eugene Vlodavsky4,10,
- Liat Appl‐Sarid11,
- Dorit Goldsher4,12,
- Reuven Bergman4,9,
- Zvi Segal2,13,
- Ora Bitterman‐Deutsch2,14 and
- Orly Avni (orly.avni{at}biu.ac.il)*,2
- 1Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel
- 2Faculty of Medicine in the Galilee, Bar‐Ilan University, Safed, Israel
- 3Metabolic Disease Unit, Rambam Health Care Campus, Haifa, Israel
- 4Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
- 5Department of Pediatric Cardiology, Rambam Health Care Campus, Haifa, Israel
- 6The Winter Genetic Institute, Bnei Zion Medical Center, Haifa, Israel
- 7Pediatric Cardiology Clinic, Bnei Zion Medical Center, Haifa, Israel
- 8The Genetic Institute, Ha'emek Medical Center, Afula, Israel
- 9Department of Dermatology, Rambam Health Care Campus, Haifa, Israel
- 10Department of Pathology, Rambam Health Care Campus, Haifa, Israel
- 11Department of Pathology, Galilee Medical Center, Nahariya, Israel
- 12Department of Diagnostic Imaging, Rambam Health Care Campus, Haifa, Israel
- 13Department of Ophthalmology, Galilee Medical Center, Nahariya, Israel
- 14Dermatology Clinic, Galilee Medical Center, Nahariya, Israel
- ↵*
Corresponding author. Tel: +972 4 9107493; E‐mail: falikmd.genetics{at}gmail.com
Corresponding author. Tel: +972 72 2644921; E‐mail: orly.avni{at}biu.ac.il
↵† These authors contributed equally to this work
A new cardio‐cutaneous syndrome associated with fatal dilated cardiomyopathy is discovered in children with sequence variations in PPP1R13L, which encodes for iASPP.
Synopsis
A new cardio‐cutaneous syndrome associated with fatal dilated cardiomyopathy is discovered in children with sequence variations in PPP1R13L, which encodes for iASPP.
Patient skin‐derived fibroblasts are hypersensitive to inflammatory stimuli, responding with NF‐κB‐dependent high expression levels of pro‐inflammatory cytokines.
In a murine model, the affected hearts are associated with pro‐inflammatory transcriptional programs starting early after birth.
Further abnormal increase happens with age and in response to inflammatory triggers.
Sublethal doses of LPS are fatal in the murine model.
EMBO Mol Med (2017) 9: 319–336
- Received April 20, 2016.
- Revision received December 5, 2016.
- Accepted December 12, 2016.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
- Irene Sambri1,
- Rosa D'Alessio1,
- Yulia Ezhova1,
- Teresa Giuliano1,
- Nicolina Cristina Sorrentino1,
- Vincenzo Cacace1,
- Maria De Risi1,2,
- Mauro Cataldi3,
- Lucio Annunziato3,
- Elvira De Leonibus1,2 and
- Alessandro Fraldi (fraldi{at}tigem.it)*,1
- 1Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
- 2Institute of Genetics and Biophysics, National Research Council, Naples, Italy
- 3Department of Neuroscience, Reproductive and Odontostomatological Sciences Federico II University, Naples, Italy
- ↵*Corresponding author. Tel: +39 081 19230632; Fax: +39 081 5609877; E‐mail: fraldi{at}tigem.it
Neurodegeneration associated with lysosomal dysfunction in lysosomal storage disorders (LSDs) may be linked to impaired presynaptic maintenance initiated by a reduction in α‐synuclein and CSPα levels at nerve terminals.
Synopsis
Neurodegeneration associated with lysosomal dysfunction in lysosomal storage disorders (LSDs) may be linked to impaired presynaptic maintenance initiated by a reduction in α‐synuclein and CSPα levels at nerve terminals.
α‐Synuclein and cysteine string protein (CSP)α are two key chaperones, which ensure efficient SNARE complex formation and synaptic vesicle recycling by maintaining physiological SNARE levels at nerve terminals.
Lysosomal dysfunction causes both the accumulation of undegraded α‐synuclein in insoluble aggregates perikarya and the enhanced proteasomal degradation of CSPα.
The unbalanced proteostasis results in the simultaneous depletion of α‐synuclein and CSPα at nerve terminals. This in turn caused a reduction in presynaptic SNARE levels, thus leading to synaptic dysfunction.
Viral‐mediated CSPα overexpression in a mouse model of mucopolysaccharidosis type IIIA mice (a severe neurodegenerative LSD) exerted a protective action against neurodegeneration by re‐establishing efficient SNARE complex formation and improving presynaptic function.
EMBO Mol Med (2017) 9: 112–132
- Received August 18, 2016.
- Revision received October 12, 2016.
- Accepted October 20, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome
- Marta Luna‐Sánchez (martalunasan{at}ugr.es)*,1,2,†,
- Agustín Hidalgo‐Gutiérrez1,2,†,
- Tatjana M Hildebrandt3,
- Julio Chaves‐Serrano2,
- Eliana Barriocanal‐Casado1,2,
- Ángela Santos‐Fandila4,
- Miguel Romero5,
- Ramy KA Sayed2,6,
- Juan Duarte5,
- Holger Prokisch7,
- Markus Schuelke8,
- Felix Distelmaier9,
- Germaine Escames1,2,
- Darío Acuña‐Castroviejo1,2 and
- Luis C López (luisca{at}ugr.es)*,1,2
- 1Departmento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain
- 2Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain
- 3Institut für Pflanzengenetik, Leibniz Universität Hannover, Hannover, Germany
- 4Abbott Nutrition, R&D, Abbott Laboratories, Granada, Spain
- 5Departmento de Farmacología, Facultad de Farmacia, Instituto de Investigación Biosanitaria de Granada, Universidad de Granada, Granada, Spain
- 6Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt
- 7Institute of Human Genetics, Technische Universität München, München, Germany
- 8Department of Neuropediatrics, Charité‐Universitätsmedizin Berlin, Berlin, Germany
- 9Department of General Pediatrics, Heinrich‐Heine‐University, Düsseldorf, Germany
- ↵*
Corresponding author. Tel: +34 958241000 ext 20197; E‐mail: martalunasan{at}ugr.es
Corresponding author. Tel: +34 958241000 ext 20197; E‐mail: luisca{at}ugr.es
↵† These authors contributed equally to this work
Disruption of the mitochondrial hydrogen sulfide oxidation pathway is identified as a new pathomechanism associated with primary CoQ deficiency. These findings may help explain the clinical heterogeneity of this syndrome.
Synopsis
Disruption of the mitochondrial hydrogen sulfide oxidation pathway is identified as a new pathomechanism associated with primary CoQ deficiency. These findings may help explain the clinical heterogeneity of this syndrome.
For the first time, disruption of mitochondrial sulfide metabolism is found to be associated with primary CoQ deficiency.
Sulfide:quinone oxidoreductase (SQR) deficiency was related to residual CoQ levels and, as a consequence, thiosulfate sulfurtransferase (TST) activity was increased and the levels of thiols were modified.
Due to the accumulation of hydrogen sulfide, the levels of certain neurotransmitters in the cerebrum of Coq9R239X mice were altered and the blood pressure was reduced.
EMBO Mol Med (2017) 9: 78–95
- Received February 25, 2016.
- Revision received October 17, 2016.
- Accepted October 19, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway
- Marcello Ziosi1,†,
- Ivano Di Meo2,†,
- Giulio Kleiner1,
- Xing‐Huang Gao3,
- Emanuele Barca1,4,
- Maria J Sanchez‐Quintero1,
- Saba Tadesse1,
- Hongfeng Jiang5,
- Changhong Qiao5,
- Richard J Rodenburg6,
- Emmanuel Scalais7,
- Markus Schuelke8,
- Belinda Willard9,
- Maria Hatzoglou3,
- Valeria Tiranti (valeria.tiranti{at}istituto-besta.it)*,2,‡ and
- Catarina M Quinzii (cmq2101{at}cumc.columbia.edu)*,1,‡
- 1Department of Neurology, Columbia University Medical Center, New York, NY, USA
- 2Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “Carlo Besta”, Milan, Italy
- 3Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
- 4Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
- 5Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY, USA
- 6Department of Pediatrics, Radboud Center for Mitochondrial Medicine (RCMM), RadboudUMC, Nijmegen, The Netherlands
- 7Division of Paediatric Neurology, Department of Paediatrics, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg
- 8Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité‐Universitätsmedizin Berlin, Berlin, Germany
- 9Mass Spectrometry Laboratory for Protein Sequencing, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- ↵*
Corresponding author. Tel: +39 02 23942633; Fax: +39 02 23942619; E‐mail: valeria.tiranti{at}istituto-besta.it
Corresponding author. Tel: +1 212 305 1637; Fax: +1 212 305 3986; E‐mail: cmq2101{at}cumc.columbia.edu
Coenzyme Q (CoQ) is an electron acceptor for sulfide‐quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Lack of CoQ is here shown to cause impairment of hydrogen sulfide oxidation in vitro and in vivo.
Synopsis
Coenzyme Q (CoQ) is an electron acceptor for sulfide‐quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Lack of CoQ is here shown to cause impairment of hydrogen sulfide oxidation in vitro and in vivo.
Reduced levels of CoQ in vitro cause impairment of the hydrogen sulfide oxidation pathway and increased protein persulfhydration levels.
Reduced levels of CoQ in vivo impair the sulfide oxidation pathway determining accumulation of sulfides and consequent inhibition of short‐chain acyl‐CoA dehydrogenase.
EMBO Mol Med (2017) 9: 96–111
- Received February 29, 2016.
- Revision received September 15, 2016.
- Accepted October 19, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency
- Antonino Montalbano1,
- Lonny Juergensen2,
- Ralph Roeth1,
- Birgit Weiss1,
- Maki Fukami3,
- Susanne Fricke‐Otto4,
- Gerhard Binder5,
- Tsutomu Ogata6,
- Eva Decker7,
- Gudrun Nuernberg8,9,
- David Hassel2 and
- Gudrun A Rappold (gudrun.rappold{at}med.uni-heidelberg.de)*,1,10
- 1Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany
- 2Department of Internal Medicine III ‐ Cardiology, Heidelberg University Hospital, Heidelberg, Germany
- 3Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
- 4Children's Hospital Krefeld, Krefeld, Germany
- 5Children's Hospital, University of Tübingen, Tübingen, Germany
- 6Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
- 7Bioscientia Center for Human Genetics, Ingelheim, Germany
- 8Center for Molecular Medicine, Cologne, Germany
- 9Cologne Center for Genomics, Cologne, Germany
- 10Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, Heidelberg, Germany
- ↵*Corresponding author. Tel: +49 6221 565059; E‐mail: gudrun.rappold{at}med.uni-heidelberg.de
SHOX mutations lead to SHOX deficiency, a disorder mostly characterized by isolated short stature and skeletal dysplasia. Co‐occurrence of CYP26C1 and SHOX mutations in patients and CYP26C1 loss in zebrafish experiments support a role for CYP26C1 variants in SHOX genotype modulation.
Synopsis
SHOX mutations lead to SHOX deficiency, a disorder mostly characterized by isolated short stature and skeletal dysplasia. Co‐occurrence of CYP26C1 and SHOX mutations in patients and CYP26C1 loss in zebrafish experiments support a role for CYP26C1 variants in SHOX genotype modulation.
Damaging mutations in SHOX and the retinoic acid‐degrading enzyme CYP26C1 co‐occur in severely affected SHOX deficiency individuals.
CYP26C1 is expressed in primary chondrocytes and zebrafish embryos pectoral fins, suggesting that it may regulate retinoic acid levels during limb development.
Loss of CYP26C1 in zebrafish embryos leads to increased retinoic levels, reduced SHOX expression, and shortened pectoral fins.
CYP26C1 acts as genetic modifier of SHOX deficiency by regulating retinoic acid intracellular levels upstream of SHOX in the retinoic acid signalling pathway.
Retinoic acid represents the most active biological form of vitamin A. Manipulating vitamin A metabolism in SHOX deficiency patients may alleviate the skeletal abnormalities of this condition.
EMBO Mol Med (2016) 8: 1455–1469
- Received May 22, 2016.
- Revision received September 28, 2016.
- Accepted October 10, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS
- Seiji Watanabe1,
- Hristelina Ilieva2,3,
- Hiromi Tamada4,
- Hanae Nomura1,
- Okiru Komine1,
- Fumito Endo1,
- Shijie Jin1,
- Pedro Mancias5,
- Hiroshi Kiyama4 and
- Koji Yamanaka (kojiyama{at}riem.nagoya-u.ac.jp)*,1
- 1Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan
- 2Houston Methodist Hospital, Houston, TX, USA
- 3Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
- 4Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
- 5Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA
- ↵*Corresponding author. Tel: +81 52 789 3865; Fax: +81 52 789 3891; E‐mail: kojiyama{at}riem.nagoya-u.ac.jp
Mitochondria‐associated membranes (MAM) are contact sites between endoplasmic reticulum and mitochondria and play a key role in cellular homeostasis. Here, disruption of the MAM is shown to be tightly involved in the pathology of amyotrophic lateral sclerosis (ALS).
Synopsis
Mitochondria‐associated membranes (MAM) are contact sites between endoplasmic reticulum and mitochondria, and play a key role in cellular homeostasis. Here, disruption of the MAM is shown to be tightly involved in the pathology of amyotrophic lateral sclerosis (ALS).
A novel ALS‐linked SIGMAR1 mutation, L95fs, is identified.
ALS‐linked sigma 1 receptor (Sig1R) mutants are unstable and non‐functional, indicating loss‐of‐function mechanism in SIGMAR1‐linked ALS.
Mutant SOD1 proteins are accumulated in the MAM, and a loss of Sig1R exacerbated the disease in mutant SOD1 transgenic mice.
Collapse of the MAM is a common pathological hallmark both in SOD1‐ and SIGMAR1‐linked ALS mouse models.
The selective enrichment of inositol triphosphate receptor type 3 (IP3R3) in the MAM of motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.
EMBO Mol Med (2016) 8: 1421–1437
- Received March 14, 2016.
- Revision received September 21, 2016.
- Accepted September 27, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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