RESUMEN
BACKGROUND: Mitochondrial encephalomyopathy caused by bi-allelic deleterious variants in TARS2 is rare. To date, only two pedigrees were reported in the literature and the connection between the gene and disease needs further study. CASE PRESENTATION: We report one infant who presented with limb hypertonia, epilepsy, developmental delay, and increased serum lactate from a non-consanguineous Chinese family. Whole-genome sequencing was performed to help to underlie the cause. We identified compound heterozygous variants c.470C > G, p.Thr157Arg and c.2143G > A, p.Glu715Lys in TARS2 and the variants were confirmed by Sanger sequencing. The patient was diagnosed with combined oxidative phosphorylation deficiency 21 according to the Online Mendelian Inheritance in Man (OMIM) database based on the clinical data and the deleterious effect of the two variants in TARS2 predicted by in silico tools. CONCLUSIONS: We presented one case diagnosed with combined oxidative phosphorylation deficiency 21 based on clinical characteristics and genetic analysis. This is the first case in China and the fourth case in the world based on our document retrieval. This study facilitates the understanding of combined oxidative phosphorylation deficiency disease and demonstrates that the next-generation sequencing has a high potential to study inherited disease with high phenotypic heterogeneity and genetic heterogeneity including mitochondrial diseases such as combined oxidative phosphorylation deficiency.
Asunto(s)
Discapacidades del Desarrollo/genética , Epilepsia/genética , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/genética , Mutación , Treonina-ARNt Ligasa/genética , Pueblo Asiatico , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/etnología , Discapacidades del Desarrollo/patología , Epilepsia/diagnóstico , Epilepsia/etnología , Epilepsia/patología , Familia , Expresión Génica , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Ácido Láctico/sangre , Masculino , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/etnología , Enfermedades Mitocondriales/patología , Encefalomiopatías Mitocondriales/diagnóstico , Encefalomiopatías Mitocondriales/etnología , Encefalomiopatías Mitocondriales/patología , Linaje , Treonina-ARNt Ligasa/deficienciaRESUMEN
OBJECTIVE: Understanding the mechanisms regulating normal and pathological angiogenesis is of great scientific and clinical interest. In this report, we show that mutations in 2 different aminoacyl-transfer RNA synthetases, threonyl tRNA synthetase (tars(y58)) or isoleucyl tRNA synthetase (iars(y68)), lead to similar increased branching angiogenesis in developing zebrafish. APPROACH AND RESULTS: The unfolded protein response pathway is activated by aminoacyl-transfer RNA synthetase deficiencies, and we show that unfolded protein response genes atf4, atf6, and xbp1, as well as the key proangiogenic ligand vascular endothelial growth factor (vegfaa), are all upregulated in tars(y58) and iars(y68) mutants. Finally, we show that the protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 arm of the unfolded protein response pathway is necessary for both the elevated vegfaa levels and increased angiogenesis observed in tars(y58) mutants. CONCLUSIONS: Our results suggest that endoplasmic reticulum stress acts as a proangiogenic signal via unfolded protein response pathway-dependent upregulation of vegfaa.