Combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA) is a neurometabolic disorder (OMIM: 615182), usually lethal in the first years of life. By whole exome sequencing several missense mutations in the SLC25A1 gene, encoding the mitochondrial citrate carrier (CIC), were identified in patients, whose biochemical hallmark is combined D-2- and L-2-hydroxyglutaric aciduria. The in silico modeling investigations indicated that the pathogenic SLC25A1 mutations would have a deleterious effect on protein function, affecting either substrate binding to the transporter or its translocation mechanism. In addition, the 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 implemented the in silico scoring system with the functional assay to analyze the importance of residues affected by all 17 missense variants detected in a total of 26 CIC-deficient patients, showing reduced activities of varying degrees. This allowed not only a clinical and biochemical overview of the D/L-2-HGA patients but also phenotype–genotype correlation studies.
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|Titolo:||Functional analysis of mitochondrial citrate carrier (SLC25A1) variants linked to combined D-2- and L-2-hydroxyglutaric aciduria.|
PALMIERI, Luigi (Corresponding)
|Data di pubblicazione:||2018|
|Appare nelle tipologie:||4.3 Poster|