An overview of combined D-2- and L-2-hydroxyglutaric aciduria: functional analysis of CIC variants

Ana Pop, Monique Williams, Eduard A. Struys, Magnus Monné, Erwin E.W. Jansen, Anna de Grassi, Warsha A. Kanhai, Pasquale Scarcia, Matilde R.Fernandez Ojeda, Vito Porcelli, Silvy J.M. van Dooren, Pascal Lennertz, Benjamin Nota, Jose E. Abdenur, David Coman, Anibh Martin Das, Areeg El-Gharbawy, Jean Marc Nuoffer, Branka Polic, René SanterNatalie Weinhold, Britton Zuccarelli, Ferdinando Palmieri, Luigi Palmieri, Gajja S. Salomons*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA) is a devastating neurometabolic disorder, usually lethal in the first years of life. Autosomal recessive mutations in the SLC25A1 gene, which encodes the mitochondrial citrate carrier (CIC), were previously detected in patients affected with combined D/L-2-HGA. We showed that transfection of deficient fibroblasts with wild-type SLC25A1 restored citrate efflux and decreased intracellular 2-hydroxyglutarate levels, confirming that deficient CIC is the cause of D/L-2-HGA. We developed and implemented a functional assay and applied it to all 17 missense variants detected in a total of 26 CIC-deficient patients, including eight novel cases, showing reduced activities of varying degrees. In addition, we analyzed the importance of residues affected by these missense variants using our existing scoring system. This allowed not only a clinical and biochemical overview of the D/L-2-HGA patients but also phenotype–genotype correlation studies.

Original languageEnglish
Pages (from-to)169-180
Number of pages12
JournalJournal of Inherited Metabolic Disease
Volume41
Issue number2
DOIs
Publication statusPublished - 1 Mar 2018

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