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

Pop, Ana, Williams, Monique, Struys, Eduard A., Monné, Magnus, Jansen, Erwin E. W., De Grassi, Anna, Kanhai, Warsha A., Scarcia, Pasquale, Ojeda, Matilde R. Fernandez, Porcelli, Vito, van Dooren, Silvy J. M., Lennertz, Pascal, Nota, Benjamin, Abdenur, Jose E., Coman, David, Das, Anibh Martin, El-Gharbawy, Areeg, Nuoffer, Jean-Marc, Polic, Branka, Santer, René, Weinhold, Natalie, Zuccarelli, Britton, Palmieri, Ferdinando, Palmieri, Luigi and Salomons, Gajja S. (2017) An overview of combined D-2- and L-2-hydroxyglutaric aciduria: functional analysis of CIC variants. Journal of Inherited Metabolic Disease, 41 2: 169-180. doi:10.1007/s10545-017-0106-7

Author Pop, Ana
Williams, Monique
Struys, Eduard A.
Monné, Magnus
Jansen, Erwin E. W.
De Grassi, Anna
Kanhai, Warsha A.
Scarcia, Pasquale
Ojeda, Matilde R. Fernandez
Porcelli, Vito
van Dooren, Silvy J. M.
Lennertz, Pascal
Nota, Benjamin
Abdenur, Jose E.
Coman, David
Das, Anibh Martin
El-Gharbawy, Areeg
Nuoffer, Jean-Marc
Polic, Branka
Santer, René
Weinhold, Natalie
Zuccarelli, Britton
Palmieri, Ferdinando
Palmieri, Luigi
Salomons, Gajja S.
Title An overview of combined D-2- and L-2-hydroxyglutaric aciduria: functional analysis of CIC variants
Journal name Journal of Inherited Metabolic Disease   Check publisher's open access policy
ISSN 1573-2665
Publication date 2017-12-13
Year available 2017
Sub-type Article (original research)
DOI 10.1007/s10545-017-0106-7
Open Access Status DOI
Volume 41
Issue 2
Start page 169
End page 180
Total pages 12
Place of publication Dordrecht, GX Netherlands
Publisher Springer
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
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.
Keyword Krebs cycle intermediates
Mitochondrial citrate carrier
Residue specific score
Structural homology
Structure-function correlations
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID GEP14141
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Medicine Publications
Version Filter Type
Citation counts: Scopus Citation Count Cited 0 times in Scopus Article
Google Scholar Search Google Scholar
Created: Wed, 20 Dec 2017, 12:14:50 EST