TY - JOUR
T1 - An overview of combined D-2- and L-2-hydroxyglutaric aciduria: functional analysis of CIC variants
T2 - functional analysis of CIC variants
AU - Pop, Ana
AU - Williams, Monique
AU - Struys, Eduard A.
AU - Monné, Magnus
AU - Jansen, Erwin E. W.
AU - de Grassi, Anna
AU - Kanhai, Warsha A.
AU - Scarcia, Pasquale
AU - Ojeda, Matilde R. Fernandez
AU - Porcelli, Vito
AU - van Dooren, Silvy J. M.
AU - Lennertz, Pascal
AU - Nota, Benjamin
AU - Abdenur, Jose E.
AU - Coman, David
AU - Das, Anibh Martin
AU - el-Gharbawy, Areeg
AU - Nuoffer, Jean-Marc
AU - Polic, Branka
AU - Santer, René
AU - Weinhold, Natalie
AU - Zuccarelli, Britton
AU - Palmieri, Ferdinando
AU - Palmieri, Luigi
AU - Salomons, Gajja S.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
KW - Krebs cycle intermediates
KW - Mitochondrial citrate carrier
KW - Residue specific score
KW - SLC25A1
KW - Structural homology
KW - Structure-function correlations
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85038021420&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29238895
UR - http://www.scopus.com/inward/record.url?scp=85038021420&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s10545-017-0106-7
DO - https://doi.org/10.1007/s10545-017-0106-7
M3 - Article
C2 - 29238895
SN - 0141-8955
VL - 41
SP - 169
EP - 180
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 2
ER -