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An overview of combined D‐2‐ and L‐2‐hydroxyglutaric aciduria: functional analysis of CIC variants
Author(s) -
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,
Dooren Silvy J. M.,
Lennertz Pascal,
Nota Benjamin,
Abdenur Jose E.,
Coman David,
Das Anibh Martin,
ElGharbawy Areeg,
Nuoffer JeanMarc,
Polic Branka,
Santer René,
Weinhold Natalie,
Zuccarelli Britton,
Palmieri Ferdinando,
Palmieri Luigi,
Salomons Gajja S.
Publication year - 2018
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-017-0106-7
Subject(s) - missense mutation , phenotype , genotype , gene , transfection , genotype phenotype distinction , genetics , mutation , intracellular , compound heterozygosity , microbiology and biotechnology , biology , medicine , chemistry
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.