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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Detalles Bibliográficos
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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/174390
Acceso en línea:https://hdl.handle.net/2445/174390
Access Level:acceso abierto
Palabra clave:Errors congènits del metabolisme
Fisiologia patològica
Inborn errors of metabolism
Pathological physiology
Descripción
Sumario: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.

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