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

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.Neuropediatrics. 2000 Jun;31(3):137-40. (PMID: 10963100); J Inherit Metab Dis. 2014 Sep;37(5):775-81. (PMID: 24687295); J Biol Chem. 2008 Oct 17;283(42):28445-53. (PMID: 18682385); Pflugers Arch. 2004 Feb;447(5):689-709. (PMID: 14598172); Mol Genet Metab. 2012 Apr;105(4):596-601. (PMID: 22281021); Prog Biophys Mol Biol. 1996;66(2):113-39. (PMID: 9175426); Arch Biochem Biophys. 1989 Apr;270(1):1-14. (PMID: 2648994); JIMD Rep. 2016;30:73-79. (PMID: 27306203); Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2617-22. (PMID: 16469842); Clin Chem. 2004 Aug;50(8):1391-5. (PMID: 15166110); Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):E426-34. (PMID: 24474793); J Neuromuscul Dis. 2014;1(1):75-90. (PMID: 26870663); Am J Hum Genet. 2013 Apr 4;92(4):627-31. (PMID: 23561848); FEBS Lett. 2010 May 3;584(9):1931-9. (PMID: 19861126); FEBS Lett. 1994 Jun 6;346(1):48-54. (PMID: 8206158); J Biol Chem. 1993 Jun 25;268(18):13682-90. (PMID: 8514800); Hum Genet. 2016 Jan;135(1):21-30. (PMID: 26541337); Nature. 2003 Nov 6;426(6962):39-44. (PMID: 14603310); J Inherit Metab Dis. 2005;28(6):1149-50. (PMID: 16435212); Methods Enzymol. 2003;374:461-91. (PMID: 14696385); Biol Chem. 2014 Apr;395(4):387-99. (PMID: 24445237); Molecules. 2017 Feb 28;22(3):. (PMID: 28264506); J Biol Chem. 2012 Mar 9;287(11):7925-34. (PMID: 22262851); Metab Eng. 2017 Sep;43(Pt B):198-207. (PMID: 27856334); J Biol Chem. 2007 Jun 8;282(23):17210-20. (PMID: 17400551); Nat Genet. 2015 Aug;47(8):926-32. (PMID: 26168012); J Med Genet. 2013 Apr;50(4):240-5. (PMID: 23393310); Essays Biochem. 2010;47:37-52. (PMID: 20533899); J Inherit Metab Dis. 2014 Jul;37(4):565-75. (PMID: 24797559); Am J Hum Genet. 2016 Dec 1;99(6):1405. (PMID: 27912046); Biochim Biophys Acta. 2016 Oct;1863(10 ):2362-78. (PMID: 26968366); Plant J. 2011 Apr;66(1):161-81. (PMID: 21443630); Mol Aspects Med. 2013 Apr-Jun;34(2-3):465-84. (PMID: 23266187); JIMD Rep. 2015;19:111-5. (PMID: 25614306); Bioessays. 2009 Jan;31(1):10-20. (PMID: 19153992); Cell Mol Life Sci. 2014 Jan;71(2):349-64. (PMID: 23800987). Linking ISSN: 01418955. Subset: MEDLINE; Grant Information: GEP14141 International Fondazione Telethon; INTEROMICS flagship project International Consiglio Nazionale delle Ricerche (IT) Date of Electronic Publication: 2017 Dec 13. Current Imprints: Publication: 2019- : [Hoboken, NJ] : Wiley; Original Imprints: Publication: [Lancaster, Eng.] MTP Press. <br />