Clinical presentation and proteomic signature of patients with TANGO2 mutations

Mingirulli, Nadja; Pyle, Angela; Hathazi, Denisa; Alston, Charlotte L.; Kohlschmidt, Nicolai; O'Grady, Gina; Waddell, Leigh; Evesson, Frances; Cooper, Sandra B. T.; Turner, Christian; Duff, Jennifer; Topf, Ana; Yubero, Delia; Jou, Cristina; Nascimento, Andrés; Ortez, Carlos Ignacio; García Cazorla, Àngels; Gross, Claudia; O'Callaghan, Maria; Santra, Saikat; Preece, Maryanne A.; Champion, Michael; Korenev, Sergei; Chronopoulou, Efsthatia; Anirban, Majumdar; Pierre, Germaine; McArthur, Daniel; Thompson, Kyle; Navas, Placido; Ribes Rubió, Maria Antònia; Tort, Frederic; Schlüter, Agatha; Pujol Onofre, Aurora; Montero, Raquel; Sarquella Brugada, Georgia; Lochmüller, Hanns; Jiménez Mallebrera, Cecilia; Taylor, Robert W.; Artuch Iriberri, Rafael; Kirschner, Janbernd; Grünert, Sarah C.; Roos, Andreas; Horvath, Rita

Clinical presentation and proteomic signature of patients with TANGO2 mutations

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive dec...

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Autores:	Mingirulli, Nadja, Pyle, Angela, Hathazi, Denisa, Alston, Charlotte L., Kohlschmidt, Nicolai, O'Grady, Gina, Waddell, Leigh, Evesson, Frances, Cooper, Sandra B. T., Turner, Christian, Duff, Jennifer, Topf, Ana, Yubero, Delia, Jou, Cristina, Nascimento, Andrés, Ortez, Carlos Ignacio, García Cazorla, Àngels, Gross, Claudia, O'Callaghan, Maria, Santra, Saikat, Preece, Maryanne A., Champion, Michael, Korenev, Sergei, Chronopoulou, Efsthatia, Anirban, Majumdar, Pierre, Germaine, McArthur, Daniel, Thompson, Kyle, Navas, Placido, Ribes Rubió, Maria Antònia, Tort, Frederic, Schlüter, Agatha, Pujol Onofre, Aurora, Montero, Raquel, Sarquella Brugada, Georgia, Lochmüller, Hanns, Jiménez Mallebrera, Cecilia, Taylor, Robert W., Artuch Iriberri, Rafael, Kirschner, Janbernd, Grünert, Sarah C., Roos, Andreas, Horvath, Rita
Formato:	artículo
Estado:	Versión publicada
Fecha de publicación:	2019
País:	España
Recursos:	Universidad de Barcelona
Repositorio:	Dipòsit Digital de la UB
OAI Identifier:	oai:diposit.ub.edu:2445/174390
Acesso em linha:	https://hdl.handle.net/2445/174390
Access Level:	acceso abierto
Palavra-chave:	Errors congènits del metabolisme Fisiologia patològica Inborn errors of metabolism Pathological physiology

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spelling	Clinical presentation and proteomic signature of patients with TANGO2 mutationsMingirulli, NadjaPyle, AngelaHathazi, DenisaAlston, Charlotte L.Kohlschmidt, NicolaiO'Grady, GinaWaddell, LeighEvesson, FrancesCooper, Sandra B. T.Turner, ChristianDuff, JenniferTopf, AnaYubero, DeliaJou, CristinaNascimento, AndrésOrtez, Carlos IgnacioGarcía Cazorla, ÀngelsGross, ClaudiaO'Callaghan, MariaSantra, SaikatPreece, Maryanne A.Champion, MichaelKorenev, SergeiChronopoulou, EfsthatiaAnirban, MajumdarPierre, GermaineMcArthur, DanielThompson, KyleNavas, PlacidoRibes Rubió, Maria AntòniaTort, FredericSchlüter, AgathaPujol Onofre, AuroraMontero, RaquelSarquella Brugada, GeorgiaLochmüller, HannsJiménez Mallebrera, CeciliaTaylor, Robert W.Artuch Iriberri, RafaelKirschner, JanberndGrünert, Sarah C.Roos, AndreasHorvath, RitaErrors congènits del metabolismeFisiologia patològicaInborn errors of metabolismPathological physiologyTransport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10 ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.John Wiley & Sons Ltd.2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/174390Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1002/jimd.12156Journal of Inherited Metabolic Disease, 2019, vol. 43, num. 2, p. 297-308https://doi.org/10.1002/jimd.12156info:eu-repo/grantAgreement/EC/FP7/309548cc by (c) Mingirulli et al., 2019http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1743902026-05-27T06:46:51Z
dc.title.none.fl_str_mv	Clinical presentation and proteomic signature of patients with TANGO2 mutations
title	Clinical presentation and proteomic signature of patients with TANGO2 mutations
spellingShingle	Clinical presentation and proteomic signature of patients with TANGO2 mutations Mingirulli, Nadja Errors congènits del metabolisme Fisiologia patològica Inborn errors of metabolism Pathological physiology
title_short	Clinical presentation and proteomic signature of patients with TANGO2 mutations
title_full	Clinical presentation and proteomic signature of patients with TANGO2 mutations
title_fullStr	Clinical presentation and proteomic signature of patients with TANGO2 mutations
title_full_unstemmed	Clinical presentation and proteomic signature of patients with TANGO2 mutations
title_sort	Clinical presentation and proteomic signature of patients with TANGO2 mutations
dc.creator.none.fl_str_mv	Mingirulli, Nadja Pyle, Angela Hathazi, Denisa Alston, Charlotte L. Kohlschmidt, Nicolai O'Grady, Gina Waddell, Leigh Evesson, Frances Cooper, Sandra B. T. Turner, Christian Duff, Jennifer Topf, Ana Yubero, Delia Jou, Cristina Nascimento, Andrés Ortez, Carlos Ignacio García Cazorla, Àngels Gross, Claudia O'Callaghan, Maria Santra, Saikat Preece, Maryanne A. Champion, Michael Korenev, Sergei Chronopoulou, Efsthatia Anirban, Majumdar Pierre, Germaine McArthur, Daniel Thompson, Kyle Navas, Placido Ribes Rubió, Maria Antònia Tort, Frederic Schlüter, Agatha Pujol Onofre, Aurora Montero, Raquel Sarquella Brugada, Georgia Lochmüller, Hanns Jiménez Mallebrera, Cecilia Taylor, Robert W. Artuch Iriberri, Rafael Kirschner, Janbernd Grünert, Sarah C. Roos, Andreas Horvath, Rita
author	Mingirulli, Nadja
author_facet	Mingirulli, Nadja Pyle, Angela Hathazi, Denisa Alston, Charlotte L. Kohlschmidt, Nicolai O'Grady, Gina Waddell, Leigh Evesson, Frances Cooper, Sandra B. T. Turner, Christian Duff, Jennifer Topf, Ana Yubero, Delia Jou, Cristina Nascimento, Andrés Ortez, Carlos Ignacio García Cazorla, Àngels Gross, Claudia O'Callaghan, Maria Santra, Saikat Preece, Maryanne A. Champion, Michael Korenev, Sergei Chronopoulou, Efsthatia Anirban, Majumdar Pierre, Germaine McArthur, Daniel Thompson, Kyle Navas, Placido Ribes Rubió, Maria Antònia Tort, Frederic Schlüter, Agatha Pujol Onofre, Aurora Montero, Raquel Sarquella Brugada, Georgia Lochmüller, Hanns Jiménez Mallebrera, Cecilia Taylor, Robert W. Artuch Iriberri, Rafael Kirschner, Janbernd Grünert, Sarah C. Roos, Andreas Horvath, Rita
author_role	author
author2	Pyle, Angela Hathazi, Denisa Alston, Charlotte L. Kohlschmidt, Nicolai O'Grady, Gina Waddell, Leigh Evesson, Frances Cooper, Sandra B. T. Turner, Christian Duff, Jennifer Topf, Ana Yubero, Delia Jou, Cristina Nascimento, Andrés Ortez, Carlos Ignacio García Cazorla, Àngels Gross, Claudia O'Callaghan, Maria Santra, Saikat Preece, Maryanne A. Champion, Michael Korenev, Sergei Chronopoulou, Efsthatia Anirban, Majumdar Pierre, Germaine McArthur, Daniel Thompson, Kyle Navas, Placido Ribes Rubió, Maria Antònia Tort, Frederic Schlüter, Agatha Pujol Onofre, Aurora Montero, Raquel Sarquella Brugada, Georgia Lochmüller, Hanns Jiménez Mallebrera, Cecilia Taylor, Robert W. Artuch Iriberri, Rafael Kirschner, Janbernd Grünert, Sarah C. Roos, Andreas Horvath, Rita
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Errors congènits del metabolisme Fisiologia patològica Inborn errors of metabolism Pathological physiology
topic	Errors congènits del metabolisme Fisiologia patològica Inborn errors of metabolism Pathological physiology
description	Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10 ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.
publishDate	2019
dc.date.none.fl_str_mv	2019
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/174390
url	https://hdl.handle.net/2445/174390
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Reproducció del document publicat a: https://doi.org/10.1002/jimd.12156 Journal of Inherited Metabolic Disease, 2019, vol. 43, num. 2, p. 297-308 https://doi.org/10.1002/jimd.12156 info:eu-repo/grantAgreement/EC/FP7/309548
dc.rights.none.fl_str_mv	cc by (c) Mingirulli et al., 2019 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	cc by (c) Mingirulli et al., 2019 http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	John Wiley & Sons Ltd.
publisher.none.fl_str_mv	John Wiley & Sons Ltd.
dc.source.none.fl_str_mv	Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona
instname_str	Universidad de Barcelona
reponame_str	Dipòsit Digital de la UB
collection	Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score	15,300719

Clinical presentation and proteomic signature of patients with TANGO2 mutations

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