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

J Inherit Metab Dis. 2018 Mar;41(2):169-180. doi: 10.1007/s10545-017-0106-7.

Ana Pop ¹, Monique Williams ¹, Eduard A Struys ¹, Magnus Monné ² ³, Erwin E W Jansen ¹, Anna De Grassi ², Warsha A Kanhai ¹, Pasquale Scarcia ², Matilde R Fernandez Ojeda ¹, Vito Porcelli ², Silvy J M van Dooren ¹, Pascal Lennertz ¹, Benjamin Nota ¹, Jose E Abdenur ⁴ ⁵, David Coman ⁶ ⁷, Anibh Martin Das ⁸, Areeg El-Gharbawy ⁹, Jean-Marc Nuoffer ¹⁰, Branka Polic ¹¹, René Santer ¹², Natalie Weinhold ¹³, Britton Zuccarelli ¹⁴, Ferdinando Palmieri ² ¹⁵, Luigi Palmieri ¹⁶ ¹⁷, Gajja S Salomons ¹⁸

Affiliations

1 Metabolic Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, VU Medical Center Metabolic Unit PK 1X009, Postbus 7057, 1007 MB, Amsterdam, The Netherlands.
2 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy.
3 Department of Sciences, University of Basilicata, Potenza, Italy.
4 Division of Metabolic Disorders, CHOC Children's, Orange, CA, USA.
5 Department of Pediatrics, University of California at Irvine, Irvine, CA, USA.
6 Department of Metabolic Medicine, Lady Cilento Children's Hospital, Brisbane, Australia.
7 School of Medicine, University of Queensland Brisbane, Griffith University Gold Coast, Gold Coast, Australia.
8 Clinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
9 Department of Pediatrics and Division of Medical Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
10 Division of Pediatric Endocrinology, Diabetology and Metabolism and University Institute of Clinical Chemistry, Inselspital, University Hospital, University of Bern, Bern, Switzerland.
11 Department of Pediatrics, PICU, University Hospital Centre, Split, Croatia.
12 Department of Pediatrics, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
13 Sozialpädiatrisches Zentrum, Charité Universitätsmedizin Berlin, Berlin, Germany.
14 The University of Kansas School of Medicine Salina Campus, Salina, USA.
15 Institute of Biomembranes, Bioenergetics and Molecular Biotechnology, Consiglio Nazionale delle Ricerche, Bari, Italy.
16 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy. luigi.palmieri@uniba.it.
17 Institute of Biomembranes, Bioenergetics and Molecular Biotechnology, Consiglio Nazionale delle Ricerche, Bari, Italy. luigi.palmieri@uniba.it.
18 Metabolic Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, VU Medical Center Metabolic Unit PK 1X009, Postbus 7057, 1007 MB, Amsterdam, The Netherlands. g.salomons@vumc.nl.

PMID: 29238895 DOI: 10.1007/s10545-017-0106-7

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.

Keywords

Krebs cycle intermediates; Mitochondrial citrate carrier; Residue specific score; SLC25A1; Structural homology; Structure-function correlations.

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