Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation

Sabrina Dusi, Lorella Valletta, Tobias B. Haack, Yugo Tsuchiya, Paola Venco, Sebastiano Pasqualato, Paola Goffrini, Marco Tigano, Nikita Demchenko, Thomas Wieland, Thomas Schwarzmayr, Tim M. Strom, Federica Invernizzi, Barbara Garavaglia, Allison Gregory, Lynn Sanford, Jeffrey Hamada, Conceição Bettencourt, Henry Houlden, Luisa ChiappariniGiovanna Zorzi, Manju A. Kurian, Nardo Nardocci, Holger Prokisch, Susan Hayflick, Ivan Gout, Valeria Tiranti

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA.

Original languageEnglish (US)
Pages (from-to)11-22
Number of pages12
JournalAmerican Journal of Human Genetics
Volume94
Issue number1
DOIs
StatePublished - Jan 2 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Dusi, S., Valletta, L., Haack, T. B., Tsuchiya, Y., Venco, P., Pasqualato, S., Goffrini, P., Tigano, M., Demchenko, N., Wieland, T., Schwarzmayr, T., Strom, T. M., Invernizzi, F., Garavaglia, B., Gregory, A., Sanford, L., Hamada, J., Bettencourt, C., Houlden, H., ... Tiranti, V. (2014). Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. American Journal of Human Genetics, 94(1), 11-22. https://doi.org/10.1016/j.ajhg.2013.11.008