Year: 2019
Type: article
Study design: Case Report
Abstract: 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 Q 10 (CoQ 10 ) 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 CoQ 10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.
DOI: 10.1002/jimd.12156
Authors: Nadja Mingirulli, Angela Pyle, Denisa Hathazi, Charlotte L. Alston, Nicolai Kohlschmidt, Gina O'Grady, Leigh Waddell, Frances Evesson, Sandra B. T. Cooper, Christian Turner, Jennifer Duff, Ana Topf, Delia Yubero, Cristina Jou, Andrés Nascimento, Carlos Ortez, Angels García‐Cazorla, Claudia Gross, Maria O'Callaghan, Saikat Santra, Maryanne A. Preece, Michael Champion, Sergei Korenev, Efsthatia Chronopoulou, Majumdar Anirban, Germaine Pierre, Daniel McArthur, Kyle Thompson, Placido Navas, Antonia Ribes, Frederic Tort, Agatha Schlüter, Aurora Pujol, Raquel Montero, Georgia Sarquella, Hanns Lochmüller, Cecilia Jiménez‐Mallebrera, Robert W. Taylor, Rafael Artuch, Janbernd Kirschner, Sarah C. Grünert, Andreas Roos, Rita Horvath
Institutions: University of Freiburg, University Medical Center Freiburg, Wellcome Centre for Mitochondrial Research, Newcastle University, Leibniz Institute for Analytical Sciences - ISAS, Children's Hospital at Westmead, Westmead Hospital, The University of Sydney, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases, Institut de Recerca Sant Joan de Déu, Birmingham Women’s and Children’s NHS Foundation Trust, St Thomas' Hospital, Bristol Royal Hospital for Children, Broad Institute, Massachusetts General Hospital, Consejo Superior de Investigaciones Científicas, Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, Centro de Investigación Biomédica en Red, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Institut d'Investigació Biomédica de Bellvitge, Institució Catalana de Recerca i Estudis Avançats, University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa Hospital, University of Duisburg-Essen, University of Cambridge
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,760
Awards: G1150926281, G1368980709, G1627312097, G1790018369, G300034400, G3006725869, G3148518360, Improving the diagnosis of paediatric mitochondrial disease using high throughput sequencing technologies, G3572136757, G424704652, Can muscle biopsy be avoided for paediatric patients with suspected mitochondrial disease?, Exploring novel molecular targets in mitochondrial protein synthesis to develop treatments in mitochondrial disease., Diagnóstico molecular y patogénesis de las enfermedades mitocondriales con deficiencia de coenzima Q10, Identificación y caracterización de nuevos defectos del metabolismo energético mitocondrial asociados a aciduria 3-metilglutacónica, G7852590918, Biomedicina de sistemas para desentrañar la base molecular y para el modelado de paraplejias espásticas hereditarias, Wellcome Centre for Mitochondrial Research, G9000221922, G9000334917, Diagnóstico molecular de los defectos de la fosforilación oxidativa mitocondrial: patogénesis de las deficiencias de CoQ10, Aplicación de la proteómica y biología de sistemas al estudio del matrisoma y miRNAs en las Distrofias Musculares Congénitas.
OpenAlex ID: W2964200538