Bi-allelic Truncating Mutations in TANGO2 Cause Infancy-Onset Recurrent Metabolic Crises with Encephalocardiomyopathy

被引：78

作者：

Kremer, Laura S. ^{[1
,2
]}

Distelmaier, Felix ^{[3
]}

Alhaddad, Bader ^{[1
]}

Hempel, Maja ^{[4
]}

Iuso, Arcangela ^{[1
,2
]}

Kuepper, Clemens ^{[5
,6
,7
]}

Muehlhausen, Chris ^{[8
]}

Kovacs-Nagy, Reka ^{[1
]}

Satanovskij, Robin ^{[1
]}

Graf, Elisabeth ^{[2
]}

Berutti, Riccardo ^{[2
]}

Eckstein, Gertrud ^{[2
]}

Durbin, Richard ^{[9
]}

Sauer, Sascha ^{[10
,11
]}

Hoffmann, Georg F. ^{[12
]}

Strom, Tim M. ^{[1
,2
]}

Santer, Rene ^{[8
]}

Meitinger, Thomas ^{[1
,2
,6
]}

Klopstock, Thomas ^{[5
,6
,7
]}

Prokisch, Holger ^{[1
,2
]}

Haack, Tobias B. ^{[1
,2
]}

机构：

[1] Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany

[2] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany

[3] Univ Dusseldorf, Univ Childrens Hosp, Dept Gen Pediat Neonatol & Pediat Cardiol, D-40225 Dusseldorf, Germany

[4] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, D-20246 Hamburg, Germany

[5] Univ Munich, Dept Neurol, Friedrich Baur Inst, D-80336 Munich, Germany

[6] Munich Cluster Syst Neurol SyNergy, D-80336 Munich, Germany

[7] DZNE German Ctr Neurodegenerat Dis, D-80336 Munich, Germany

[8] Univ Med Ctr Hamburg Eppendorf, Univ Childrens Hosp, D-20246 Hamburg, Germany

[9] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[10] Max Planck Inst Mol Genet, Otto Warburg Lab, Ihnestr 73, D-14195 Berlin, Germany

[11] Univ Wurzburg, CU Syst Med, D-97080 Wurzburg, Germany

[12] Univ Heidelberg Hosp, Dept Gen Pediat, Div Pediat Metab Med & Neuropediat, D-69120 Heidelberg, Germany

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2016年 / 98卷 / 02期

关键词：

DELETION SYNDROME; MITOCHONDRIAL; DEFICIENCY; GENES;

D O I：

10.1016/j.ajhg.2015.12.009

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Molecular diagnosis of mitochondrial disorders is challenging because of extreme clinical and genetic heterogeneity. By exome sequencing, we identified three different bi-allelic truncating mutations in TANGO2 in three unrelated individuals with infancy-onset episodic metabolic crises characterized by encephalopathy, hypoglycemia, rhabdomyolysis, arrhythmias, and laboratory findings suggestive of a defect in mitochondrial fatty acid oxidation. Over the course of the disease, all individuals developed global brain atrophy with cognitive impairment and pyramidal signs. TANGO2 (transport and Golgi organization 2) encodes a protein with a putative function in redistribution of Golgi membranes into the endoplasmic reticulum in Drosophila and a mitochondrial localization has been confirmed in mice. Investigation of palmitate-dependent respiration in mutant fibroblasts showed evidence of a functional defect in mitochondrial b-oxidation. Our results establish TANGO2 deficiency as a clinically recognizable cause of pediatric disease with multiorgan involvement.

引用

页码：358 / 362

页数：5

共 11 条

[1]

Metabolic Myoglobinuria [J].

Barca, Emanuele ;

Emmanuele, Valentina ;

DiMauro, Salvatore .

CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS, 2015, 15 (10)

[2]

Functional genomics reveals genes involved in protein secretion and Golgi organization [J].

Bard, F ;

Casano, L ;

Mallabiabarrena, A ;

Wallace, E ;

Saito, K ;

Kitayama, H ;

Guizzunti, G ;

Hu, Y ;

Wendler, F ;

DasGupta, R ;

Perrimon, N ;

Malhotra, V .

NATURE, 2006, 439 (7076) :604-607

[3]

Regulation of mitochondrial fatty acid β-oxidation in human: What can we learn from inborn fatty acid β-oxidation deficiencies? [J].

Bastin, Jean .

BIOCHIMIE, 2014, 96 :113-120

[4]

COQ4 Mutations Cause a Broad Spectrum of Mitochondrial Disorders Associated with CoQ10 Deficiency [J].

Brea-Calvo, Gloria ;

Haack, Tobias B. ;

Karall, Daniela ;

Ohtake, Akira ;

Invernizzi, Federica ;

Carrozzo, Rosalba ;

Kremer, Laura ;

Dusi, Sabrina ;

Fauth, Christine ;

Scholl-Buergi, Sabine ;

Graf, Elisabeth ;

Ahting, Uwe ;

Resta, Nicoletta ;

Laforgia, Nicola ;

Verrigni, Daniela ;

Okazaki, Yasushi ;

Kohda, Masakazu ;

Martinelli, Diego ;

Freisinger, Peter ;

Strom, Tim M. ;

Meitinger, Thomas ;

Lamperti, Costanza ;

Lacson, Atilano ;

Navas, Placido ;

Mayr, Johannes A. ;

Bertini, Enrico ;

Murayama, Kei ;

Zeviani, Massimo ;

Prokisch, Holger ;

Ghezzi, Daniele .

AMERICAN JOURNAL OF HUMAN GENETICS, 2015, 96 (02) :309-317

[5]

Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement [J].

Haack, Tobias B. ;

Jackson, Christopher B. ;

Murayama, Kei ;

Kremer, Laura S. ;

Schaller, Andre ;

Kotzaeridou, Urania ;

de Vries, Maaike C. ;

Schottmann, Gudrun ;

Santra, Saikat ;

Buechner, Boriana ;

Wieland, Thomas ;

Graf, Elisabeth ;

Freisinger, Peter ;

Eggimann, Sandra ;

Ohtake, Akira ;

Okazaki, Yasushi ;

Kohda, Masakazu ;

Kishita, Yoshihito ;

Tokuzawa, Yoshimi ;

Sauer, Sascha ;

Memari, Yasin ;

Kolb-Kokocinski, Anja ;

Durbin, Richard ;

Hasselmann, Oswald ;

Cremer, Kirsten ;

Albrecht, Beate ;

Wieczorek, Dagmar ;

Engels, Hartmut ;

Hahn, Dagmar ;

Zink, Alexander M. ;

Alston, Charlotte L. ;

Taylor, Robert W. ;

Rodenburg, Richard J. ;

Trollmann, Regina ;

Sperl, Wolfgang ;

Strom, Tim M. ;

Hoffmann, Georg F. ;

Mayr, Johannes A. ;

Meitinger, Thomas ;

Bolognini, Ramona ;

Schuelke, Markus ;

Nuoffer, Jean-Marc ;

Koelker, Stefan ;

Prokisch, Holger ;

Klopstock, Thomas .

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 2015, 2 (05) :492-509

[6]

Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA [J].

Haack, Tobias B. ;

Hogarth, Penelope ;

Kruer, Michael C. ;

Gregory, Allison ;

Wieland, Thomas ;

Schwarzmayr, Thomas ;

Graf, Elisabeth ;

Sanford, Lynn ;

Meyer, Esther ;

Kara, Eleanna ;

Cuno, Stephan M. ;

Harik, Sami I. ;

Dandu, Vasuki H. ;

Nardocci, Nardo ;

Zorzi, Giovanna ;

Dunaway, Todd ;

Tarnopolsky, Mark ;

Skinner, Steven ;

Frucht, Steven ;

Hanspal, Era ;

Schrander-Stumpel, Connie ;

Heron, Delphine ;

Mignot, Cyril ;

Garavaglia, Barbara ;

Bhatia, Kailash ;

Hardy, John ;

Strom, Tim M. ;

Boddaert, Nathalie ;

Houlden, Henry H. ;

Kurian, Manju A. ;

Meitinger, Thomas ;

Prokisch, Holger ;

Hayflick, Susan J. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2012, 91 (06) :1144-1149

[7]

Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing [J].

Haack, Tobias B. ;

Haberberger, Birgit ;

Frisch, Eva-Maria ;

Wieland, Thomas ;

Iuso, Arcangela ;

Gorza, Matteo ;

Strecker, Valentina ;

Graf, Elisabeth ;

Mayr, Johannes A. ;

Herberg, Ulrike ;

Hennermann, Julia B. ;

Klopstock, Thomas ;

Kuhn, Klaus A. ;

Ahting, Uwe ;

Sperl, Wolfgang ;

Wilichowski, Ekkehard ;

Hoffmann, Georg F. ;

Tesarova, Marketa ;

Hansikova, Hana ;

Zeman, Jiri ;

Plecko, Barbara ;

Zeviani, Massimo ;

Wittig, Ilka ;

Strom, Tim M. ;

Schuelke, Markus ;

Freisinger, Peter ;

Meitinger, Thomas ;

Prokisch, Holger .

JOURNAL OF MEDICAL GENETICS, 2012, 49 (04) :277-283

[8]

Mitochondrial localization and function of a subset of 22q11 deletion syndrome candidate genes [J].

Maynard, T. M. ;

Meechan, D. W. ;

Dudevoir, M. L. ;

Gopalakrishna, D. ;

Peters, A. Z. ;

Heindel, C. C. ;

Sugimoto, T. J. ;

Wu, Y. ;

Lieberman, J. A. ;

LaMantia, A. -S. .

MOLECULAR AND CELLULAR NEUROSCIENCE, 2008, 39 (03) :439-451

[9]

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome [J].

Napoli, Eleonora ;

Tassone, Flora ;

Wong, Sarah ;

Angkustsiri, Kathleen ;

Simon, Tony J. ;

Song, Gyu ;

Giulivi, Cecilia .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2015, 290 (38) :23240-23253

[10]

A robust model for read count data in exome sequencing experiments and implications for copy number variant calling [J].

Plagnol, Vincent ;

Curtis, James ;

Epstein, Michael ;

Mok, Kin Y. ;

Stebbings, Emma ;

Grigoriadou, Sofia ;

Wood, Nicholas W. ;

Hambleton, Sophie ;

Burns, Siobhan O. ;

Thrasher, Adrian J. ;

Kumararatne, Dinakantha ;

Doffinger, Rainer ;

Nejentsev, Sergey .

BIOINFORMATICS, 2012, 28 (21) :2747-2754

← 1 2 →