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Genetics, Gene Therapy & Genetic Disease

  • Open Access
    Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome
    Sequence variation in <em>PPP1R13L</em> results in a novel form of cardio‐cutaneous syndrome
    1. Tzipora C Falik‐Zaccai (falikmd.genetics{at}gmail.com)*,1,2,
    2. Yiftah Barsheshet2,†,
    3. Hanna Mandel3,4,†,
    4. Meital Segev2,
    5. Avraham Lorber4,5,
    6. Shachaf Gelberg2,
    7. Limor Kalfon1,
    8. Shani Ben Haroush1,
    9. Adel Shalata6,
    10. Liat Gelernter‐Yaniv7,
    11. Sarah Chaim1,
    12. Dorith Raviv Shay1,
    13. Morad Khayat8,
    14. Michal Werbner2,
    15. Inbar Levi1,
    16. Yishay Shoval1,
    17. Galit Tal3,4,
    18. Stavit Shalev4,8,
    19. Eli Reuveni2,
    20. Emily Avitan‐Hersh9,
    21. Eugene Vlodavsky4,10,
    22. Liat Appl‐Sarid11,
    23. Dorit Goldsher4,12,
    24. Reuven Bergman4,9,
    25. Zvi Segal2,13,
    26. Ora Bitterman‐Deutsch2,14 and
    27. Orly Avni (orly.avni{at}biu.ac.il)*,2
    1. 1Institute of Human Genetics, Galilee Medical Center, Nahariya, Israel
    2. 2Faculty of Medicine in the Galilee, Bar‐Ilan University, Safed, Israel
    3. 3Metabolic Disease Unit, Rambam Health Care Campus, Haifa, Israel
    4. 4Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
    5. 5Department of Pediatric Cardiology, Rambam Health Care Campus, Haifa, Israel
    6. 6The Winter Genetic Institute, Bnei Zion Medical Center, Haifa, Israel
    7. 7Pediatric Cardiology Clinic, Bnei Zion Medical Center, Haifa, Israel
    8. 8The Genetic Institute, Ha'emek Medical Center, Afula, Israel
    9. 9Department of Dermatology, Rambam Health Care Campus, Haifa, Israel
    10. 10Department of Pathology, Rambam Health Care Campus, Haifa, Israel
    11. 11Department of Pathology, Galilee Medical Center, Nahariya, Israel
    12. 12Department of Diagnostic Imaging, Rambam Health Care Campus, Haifa, Israel
    13. 13Department of Ophthalmology, Galilee Medical Center, Nahariya, Israel
    14. 14Dermatology Clinic, Galilee Medical Center, Nahariya, Israel
    1. ↵* 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

    1. ↵† 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.

    • dilated cardiomyopathy
    • genetics
    • inflammation
    • myocarditis
    • PPP1R13L

    EMBO Mol Med (2017) 9: 319–336

    • Received April 20, 2016.
    • Revision received December 5, 2016.
    • Accepted December 12, 2016.

    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.

    Tzipora C Falik‐Zaccai, Yiftah Barsheshet, Hanna Mandel, Meital Segev, Avraham Lorber, Shachaf Gelberg, Limor Kalfon, Shani Ben Haroush, Adel Shalata, Liat Gelernter‐Yaniv, Sarah Chaim, Dorith Raviv Shay, Morad Khayat, Michal Werbner, Inbar Levi, Yishay Shoval, Galit Tal, Stavit Shalev, Eli Reuveni, Emily Avitan‐Hersh, Eugene Vlodavsky, Liat Appl‐Sarid, Dorit Goldsher, Reuven Bergman, Zvi Segal, Ora Bitterman‐Deutsch, Orly Avni
    Published online 01.03.2017
  • Open Access
    Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
    Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
    1. Irene Sambri1,
    2. Rosa D'Alessio1,
    3. Yulia Ezhova1,
    4. Teresa Giuliano1,
    5. Nicolina Cristina Sorrentino1,
    6. Vincenzo Cacace1,
    7. Maria De Risi1,2,
    8. Mauro Cataldi3,
    9. Lucio Annunziato3,
    10. Elvira De Leonibus1,2 and
    11. Alessandro Fraldi (fraldi{at}tigem.it)*,1
    1. 1Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
    2. 2Institute of Genetics and Biophysics, National Research Council, Naples, Italy
    3. 3Department of Neuroscience, Reproductive and Odontostomatological Sciences Federico II University, Naples, Italy
    1. ↵*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.

    • lysosomes
    • lysosomal storage disorders
    • α‐synuclein
    • CSPα
    • neurodegeneration

    EMBO Mol Med (2017) 9: 112–132

    • Received August 18, 2016.
    • Revision received October 12, 2016.
    • Accepted October 20, 2016.

    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.

    Irene Sambri, Rosa D'Alessio, Yulia Ezhova, Teresa Giuliano, Nicolina Cristina Sorrentino, Vincenzo Cacace, Maria De Risi, Mauro Cataldi, Lucio Annunziato, Elvira De Leonibus, Alessandro Fraldi
    Published online 01.01.2017
  • Open Access
    CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome
    CoQ deficiency causes disruption of mitochondrial sulfide oxidation, a new pathomechanism associated with this syndrome
    1. Marta Luna‐Sánchez (martalunasan{at}ugr.es)*,1,2,†,
    2. Agustín Hidalgo‐Gutiérrez1,2,†,
    3. Tatjana M Hildebrandt3,
    4. Julio Chaves‐Serrano2,
    5. Eliana Barriocanal‐Casado1,2,
    6. Ángela Santos‐Fandila4,
    7. Miguel Romero5,
    8. Ramy KA Sayed2,6,
    9. Juan Duarte5,
    10. Holger Prokisch7,
    11. Markus Schuelke8,
    12. Felix Distelmaier9,
    13. Germaine Escames1,2,
    14. Darío Acuña‐Castroviejo1,2 and
    15. Luis C López (luisca{at}ugr.es)*,1,2
    1. 1Departmento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain
    2. 2Instituto de Biotecnología, Centro de Investigación Biomédica, Universidad de Granada, Granada, Spain
    3. 3Institut für Pflanzengenetik, Leibniz Universität Hannover, Hannover, Germany
    4. 4Abbott Nutrition, R&D, Abbott Laboratories, Granada, Spain
    5. 5Departmento de Farmacología, Facultad de Farmacia, Instituto de Investigación Biosanitaria de Granada, Universidad de Granada, Granada, Spain
    6. 6Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt
    7. 7Institute of Human Genetics, Technische Universität München, München, Germany
    8. 8Department of Neuropediatrics, Charité‐Universitätsmedizin Berlin, Berlin, Germany
    9. 9Department of General Pediatrics, Heinrich‐Heine‐University, Düsseldorf, Germany
    1. ↵* 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

    1. ↵† 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.

    • blood pressure
    • COX
    • glutathione
    • mitochondrial disease
    • SQR

    EMBO Mol Med (2017) 9: 78–95

    • Received February 25, 2016.
    • Revision received October 17, 2016.
    • Accepted October 19, 2016.

    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.

    Marta Luna‐Sánchez, Agustín Hidalgo‐Gutiérrez, Tatjana M Hildebrandt, Julio Chaves‐Serrano, Eliana Barriocanal‐Casado, Ángela Santos‐Fandila, Miguel Romero, Ramy KA Sayed, Juan Duarte, Holger Prokisch, Markus Schuelke, Felix Distelmaier, Germaine Escames, Darío Acuña‐Castroviejo, Luis C López
    Published online 01.01.2017
  • Open Access
    Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway
    Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway
    1. Marcello Ziosi1,†,
    2. Ivano Di Meo2,†,
    3. Giulio Kleiner1,
    4. Xing‐Huang Gao3,
    5. Emanuele Barca1,4,
    6. Maria J Sanchez‐Quintero1,
    7. Saba Tadesse1,
    8. Hongfeng Jiang5,
    9. Changhong Qiao5,
    10. Richard J Rodenburg6,
    11. Emmanuel Scalais7,
    12. Markus Schuelke8,
    13. Belinda Willard9,
    14. Maria Hatzoglou3,
    15. Valeria Tiranti (valeria.tiranti{at}istituto-besta.it)*,2,‡ and
    16. Catarina M Quinzii (cmq2101{at}cumc.columbia.edu)*,1,‡
    1. 1Department of Neurology, Columbia University Medical Center, New York, NY, USA
    2. 2Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “Carlo Besta”, Milan, Italy
    3. 3Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
    4. 4Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
    5. 5Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY, USA
    6. 6Department of Pediatrics, Radboud Center for Mitochondrial Medicine (RCMM), RadboudUMC, Nijmegen, The Netherlands
    7. 7Division of Paediatric Neurology, Department of Paediatrics, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg
    8. 8Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité‐Universitätsmedizin Berlin, Berlin, Germany
    9. 9Mass Spectrometry Laboratory for Protein Sequencing, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA
    1. ↵* 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

    1. ↵† These authors contributed equally to this work

    2. ↵‡ These authors contributed equally to thus work

    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.

    • coenzyme Q
    • CoQ10
    • Pdss2
    • SQR
    • sulfides

    EMBO Mol Med (2017) 9: 96–111

    • Received February 29, 2016.
    • Revision received September 15, 2016.
    • Accepted October 19, 2016.

    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.

    Marcello Ziosi, Ivano Di Meo, Giulio Kleiner, Xing‐Huang Gao, Emanuele Barca, Maria J Sanchez‐Quintero, Saba Tadesse, Hongfeng Jiang, Changhong Qiao, Richard J Rodenburg, Emmanuel Scalais, Markus Schuelke, Belinda Willard, Maria Hatzoglou, Valeria Tiranti, Catarina M Quinzii
    Published online 01.01.2017
  • Open Access
    Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency
    Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency
    1. Antonino Montalbano1,
    2. Lonny Juergensen2,
    3. Ralph Roeth1,
    4. Birgit Weiss1,
    5. Maki Fukami3,
    6. Susanne Fricke‐Otto4,
    7. Gerhard Binder5,
    8. Tsutomu Ogata6,
    9. Eva Decker7,
    10. Gudrun Nuernberg8,9,
    11. David Hassel2 and
    12. Gudrun A Rappold (gudrun.rappold{at}med.uni-heidelberg.de)*,1,10
    1. 1Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany
    2. 2Department of Internal Medicine III ‐ Cardiology, Heidelberg University Hospital, Heidelberg, Germany
    3. 3Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
    4. 4Children's Hospital Krefeld, Krefeld, Germany
    5. 5Children's Hospital, University of Tübingen, Tübingen, Germany
    6. 6Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
    7. 7Bioscientia Center for Human Genetics, Ingelheim, Germany
    8. 8Center for Molecular Medicine, Cologne, Germany
    9. 9Cologne Center for Genomics, Cologne, Germany
    10. 10Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, Heidelberg, Germany
    1. ↵*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.

    • clinical variability
    • genetic modifiers
    • limb development
    • retinoic acid
    • skeletal dysplasia

    EMBO Mol Med (2016) 8: 1455–1469

    • Received May 22, 2016.
    • Revision received September 28, 2016.
    • Accepted October 10, 2016.

    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.

    Antonino Montalbano, Lonny Juergensen, Ralph Roeth, Birgit Weiss, Maki Fukami, Susanne Fricke‐Otto, Gerhard Binder, Tsutomu Ogata, Eva Decker, Gudrun Nuernberg, David Hassel, Gudrun A Rappold
    Published online 01.12.2016
  • Open Access
    Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS
    Mitochondria‐associated membrane collapse is a common pathomechanism in <em>SIGMAR1</em>‐ and <em>SOD1</em>‐linked ALS
    1. Seiji Watanabe1,
    2. Hristelina Ilieva2,3,
    3. Hiromi Tamada4,
    4. Hanae Nomura1,
    5. Okiru Komine1,
    6. Fumito Endo1,
    7. Shijie Jin1,
    8. Pedro Mancias5,
    9. Hiroshi Kiyama4 and
    10. Koji Yamanaka (kojiyama{at}riem.nagoya-u.ac.jp)*,1
    1. 1Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, Japan
    2. 2Houston Methodist Hospital, Houston, TX, USA
    3. 3Department of Neurology, Johns Hopkins University, Baltimore, MD, USA
    4. 4Department of Functional Anatomy and Neuroscience, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
    5. 5Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA
    1. ↵*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.

    • amyotrophic lateral sclerosis
    • inositol 1,4,5‐triphosphate receptor type 3
    • mitochondria‐associated membrane
    • sigma 1 receptor

    EMBO Mol Med (2016) 8: 1421–1437

    • Received March 14, 2016.
    • Revision received September 21, 2016.
    • Accepted September 27, 2016.

    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.

    Seiji Watanabe, Hristelina Ilieva, Hiromi Tamada, Hanae Nomura, Okiru Komine, Fumito Endo, Shijie Jin, Pedro Mancias, Hiroshi Kiyama, Koji Yamanaka
    Published online 01.12.2016
  • Open Access
    Niacin‐mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination
    Niacin‐mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination
    1. Alessandra Bolino (bolino.alessandra{at}hsr.it)*,1,2,
    2. Françoise Piguet1,2,5,
    3. Valeria Alberizzi1,2,
    4. Marta Pellegatta1,2,
    5. Cristina Rivellini1,2,
    6. Marta Guerrero‐Valero1,2,
    7. Roberta Noseda1,2,
    8. Chiara Brombin3,
    9. Alessandro Nonis3,
    10. Patrizia D'Adamo2,
    11. Carla Taveggia1,2 and
    12. Stefano Carlo Previtali1,2,4
    1. 1INSPE‐Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy
    2. 2Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
    3. 3University Centre of Statistics in the Biomedical Sciences (CUSSB), Vita‐Salute San Raffaele University, Milan, Italy
    4. 4Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
    5. 5Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Strasbourg, France
    1. ↵*Corresponding author. Tel: +39 02 26364743; Fax: +39 02 26435093; E‐mail: bolino.alessandra{at}hsr.it

    The α‐secretase TACE negatively regulates Neuregulin 1 (Nrg1) type III, a main driver of Schwann cell myelination. Enhancement of TACE activity with Niaspan/niacin reduces focal hypermyelination in Charcot–Marie–Tooth and HNPP neuropathy mouse models.

    Synopsis

    The α‐secretase TACE negatively regulates Neuregulin 1 (Nrg1) type III, a main driver of Schwann cell myelination. Enhancement of TACE activity with Niaspan/niacin reduces focal hypermyelination in Charcot–Marie–Tooth and HNPP neuropathy mouse models.

    • Downregulation of Nrg1 type III ameliorates hypermyelination in Charcot–Marie–Tooth, HNPP neuropathy and vimentin−/− mouse models.

    • Hypermyelination is reduced by Niaspan/niacin, via enhancement of TACE activity and consequent reduction of Nrg1.

    • TACE is the specific target of niacin in myelin‐forming Schwann cell/DRG co‐cultures.

    • animal models
    • Charcot–Marie–Tooth neuropathies
    • myelin
    • Neuregulin 1
    • nicotinic acid

    EMBO Mol Med (2016) 8: 1438–1454

    • Received February 27, 2016.
    • Revision received September 22, 2016.
    • Accepted October 4, 2016.

    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.

    Alessandra Bolino, Françoise Piguet, Valeria Alberizzi, Marta Pellegatta, Cristina Rivellini, Marta Guerrero‐Valero, Roberta Noseda, Chiara Brombin, Alessandro Nonis, Patrizia D'Adamo, Carla Taveggia, Stefano Carlo Previtali
    Published online 01.12.2016
  • Open Access
    TECRL: connecting sequence to consequence for a new sudden cardiac death gene
    <em>TECRL</em>: connecting sequence to consequence for a new sudden cardiac death gene
    1. Matthew D Perry1 and
    2. Jamie I Vandenberg (j.vandenberg{at}victorchang.edu.au)1
    1. 1Mark Cowley Lidwill Research Programme in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia

    The sudden unexpected death of a child is a devastating event. One of the first questions a family will ask is “Why did this happen?” In some cases, the answer may become obvious during a postmortem examination, but in up to 40% of cases, the postmortem is negative (Bagnall et al, 2016). In the last 1–2 decades, an improved understanding of the genetic basis of the primary arrhythmia syndromes, the major cause of sudden unexplained death in children with structurally normal hearts, has greatly enhanced our ability to make a postmortem diagnosis (Van Norstrand & Ackerman, 2010). Establishing an accurate genetic diagnosis can not only answer the parents' question as to why did this happen to my child, but is invaluable for cascade screening of all family members to identify other individuals harbouring the same mutation and who therefore may be at risk of sudden cardiac death. However, even after screening for all of the established genes associated with primary arrhythmia syndromes, up to two thirds of unexplained cardiac deaths will remain unsolved. Such was the case for a family of Sudanese origin with a highly malignant form of exercise‐induced arrhythmias, originally reported by Bhuiyan et al (2007).

    See also: HD Devalla et al (December 2016)

    Perry and Vandenberg comment on the paper by Devalla et al (2016) showing that homozygous loss‐of‐function mutations in the novel gene TECRL cause highly malignant exercise‐induced arrhythmias.

    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.

    Matthew D Perry, Jamie I Vandenberg
    Published online 01.12.2016
  • Open Access
    TECRL, a new life‐threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT
    <em>TECRL</em>, a new life‐threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT
    1. Harsha D Devalla (h.d.devalla{at}lumc.nl)*,1,†,
    2. Roselle Gélinas2,3,†,
    3. Elhadi H Aburawi4,†,
    4. Abdelaziz Beqqali5,†,
    5. Philippe Goyette2,
    6. Christian Freund1,6,
    7. Marie‐A Chaix2,3,
    8. Rafik Tadros2,3,5,
    9. Hui Jiang7,8,9,
    10. Antony Le Béchec10,
    11. Jantine J Monshouwer‐Kloots1,
    12. Tom Zwetsloot1,
    13. Georgios Kosmidis1,
    14. Frédéric Latour2,
    15. Azadeh Alikashani2,
    16. Maaike Hoekstra5,
    17. Jurg Schlaepfer11,
    18. Christine L Mummery1,
    19. Brian Stevenson10,
    20. Zoltan Kutalik10,12,
    21. Antoine AF de Vries13,14,
    22. Léna Rivard2,3,
    23. Arthur AM Wilde15,16,
    24. Mario Talajic2,3,
    25. Arie O Verkerk5,‡,
    26. Lihadh Al‐Gazali4,‡,
    27. John D Rioux (john.david.rioux{at}umontreal.ca)*,2,3,†,‡,
    28. Zahurul A Bhuiyan (z.a.bhuiyan{at}chuv.ch)*,17,‡ and
    29. Robert Passier (r.passier{at}lumc.nl)*,1,18,‡
    1. 1Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands
    2. 2Montreal Heart Institute, Montreal, QC, Canada
    3. 3Department of Medicine, Université de Montréal, Montreal, QC, Canada
    4. 4Department of Pediatrics, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
    5. 5Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    6. 6Leiden University Medical Center hiPSC Core Facility, Leiden, The Netherlands
    7. 7Beijing Genomics Institute, Shenzhen, China
    8. 8Shenzhen Key Laboratory of Genomics, Shenzhen, China
    9. 9The Guangdong Enterprise Key Laboratory of Human Disease Genomics, Shenzhen, China
    10. 10Vital‐IT group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
    11. 11Service de Cardiologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
    12. 12Institute of Social and Preventive Medicine, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
    13. 13Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
    14. 14ICIN‐Netherlands Heart Institute, Utrecht, The Netherlands
    15. 15Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    16. 16Princess Al‐Jawhara Al‐Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia
    17. 17Laboratoire Génétiqué Moléculaire, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
    18. 18Department of Applied Stem Cell Technologies, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
    1. ↵* Corresponding author. Tel: +31 715268889; E‐mail: h.d.devalla{at}lumc.nl
      Corresponding author. Tel: +1 5143763330 ext. 3741; E‐mail: john.david.rioux{at}umontreal.ca
      Corresponding author. Tel: +41 213143370; E‐mail: z.a.bhuiyan{at}chuv.ch
      Corresponding author. Tel: +31 534895553; E‐mail: r.passier{at}lumc.nl

    1. ↵† These authors contributed equally to this work

    2. ↵‡ These authors contributed equally to this work

    Mutations in the novel TECRL gene were identified in patients with malignant exercise‐induced arrhythmias. Increased triggered electrical activity upon stimulation in patient‐specific hiPSC‐CMs was rescued by the antiarrhythmic drug flecainide.

    Synopsis

    Mutations in the novel TECRL gene were identified in patients with malignant exercise‐induced arrhythmias. Increased triggered electrical activity upon stimulation in patient‐specific hiPSC‐CMs was rescued by the antiarrhythmic drug flecainide.

    • Trans‐2,3‐enoyl‐CoA reductase‐like (TECRL) is preferentially expressed in the heart.

    • Mutations in TECRL cause lethal arrhythmias in humans.

    • Cardiac defects in TECRL patients are characterized by overlapping features of long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).

    • Cardiomyocytes differentiated from patient‐specific human induced pluripotent stem cells (hiPSCs) recapitulate the electrical abnormalities observed in TECRL patients.

    • Arrhythmia
    • CPVT
    • iPSC
    • LQTS
    • SRD5A2L2

    EMBO Mol Med (2016) 8: 1390–1408

    • Received August 21, 2015.
    • Revision received September 20, 2016.
    • Accepted September 23, 2016.

    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.

    Harsha D Devalla, Roselle Gélinas, Elhadi H Aburawi, Abdelaziz Beqqali, Philippe Goyette, Christian Freund, Marie‐A Chaix, Rafik Tadros, Hui Jiang, Antony Le Béchec, Jantine J Monshouwer‐Kloots, Tom Zwetsloot, Georgios Kosmidis, Frédéric Latour, Azadeh Alikashani, Maaike Hoekstra, Jurg Schlaepfer, Christine L Mummery, Brian Stevenson, Zoltan Kutalik, Antoine AF de Vries, Léna Rivard, Arthur AM Wilde, Mario Talajic, Arie O Verkerk, Lihadh Al‐Gazali, John D Rioux, Zahurul A Bhuiyan, Robert Passier
    Published online 01.12.2016
  • Open Access
    Effects of ketosis in mitochondrial myopathy: potential benefits of a mitotoxic diet
    Effects of ketosis in mitochondrial myopathy: potential benefits of a mitotoxic diet
    1. Robert DS Pitceathly1,2 and
    2. Carlo Viscomi (cfv23{at}mrc-mbu.cam.ac.uk)3
    1. 1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
    2. 2Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
    3. 3MRC‐Mitochondrial Biology Unit, Cambridge, UK

    The field of mitochondrial medicine is rapidly transitioning from preclinical observation to clinical application. Translation of promising data obtained in mouse models is not always straight‐forward, however. Building on their own work showing that a ketogenic diet induces mitochondrial biogenesis and delays the onset of disease in the Deletor mouse, Ahola et al administered modified Atkins diet (mAD) to five patients with mitochondrial myopathy caused by mitochondrial DNA deletions (Ahola et al, 2016). Surprisingly, mAD did not induce mitochondrial biogenesis in patients, but rather triggered the progressive damage of muscle cells, particularly those with impaired respiratory chain activity (the ragged‐red fibres). The subsequent extensive characterisation of the metabolic and molecular profile changes observed in patients and healthy controls provides a significant advance towards understanding the feasibility of dietary modification as a treatment strategy for mitochondrial diseases.

    See also: S Ahola et al (November 2016)

    Pitceathly and Viscomi comment on a new report by Anu Suomalainen's team showing that a ketogenic modified Atkins diet induces muscle damage, especially of ragged‐red fibres, in human mitochondrial myopathic patients.

    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.

    Robert DS Pitceathly, Carlo Viscomi
    Published online 01.11.2016

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