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

Ana Pop, Monique Williams, Eduard A. Struys, Magnus Monné, Erwin E.W. Jansen, Anna de Grassi, Warsha A. Kanhai, Pasquale Scarcia, Matilde R.Fernandez Ojeda, Vito Porcelli, Silvy J.M. van Dooren, Pascal Lennertz, Benjamin Nota, Jose E. Abdenur, David Coman, Anibh Martin Das, Areeg El-Gharbawy, Jean Marc Nuoffer, Branka Polic, René Santer & 5 others Natalie Weinhold, Britton Zuccarelli, Ferdinando Palmieri, Luigi Palmieri, Gajja S. Salomons

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)169-180
Number of pages12
JournalJournal of Inherited Metabolic Disease
Volume41
Issue number2
DOIs
Publication statusPublished - 1 Mar 2018

Cite this

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. / An overview of combined D-2- and L-2-hydroxyglutaric aciduria : functional analysis of CIC variants. In: Journal of Inherited Metabolic Disease. 2018 ; Vol. 41, No. 2. pp. 169-180.
@article{ba9fcacf3bbe47f4911973f49dc290c3,
title = "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.",
keywords = "Krebs cycle intermediates, Mitochondrial citrate carrier, Residue specific score, SLC25A1, Structural homology, Structure-function correlations",
author = "Ana Pop and Monique Williams and Struys, {Eduard A.} and Magnus Monn{\'e} and Jansen, {Erwin E.W.} and {de Grassi}, Anna and Kanhai, {Warsha A.} and Pasquale Scarcia and Ojeda, {Matilde R.Fernandez} and Vito Porcelli and {van Dooren}, {Silvy J.M.} and Pascal Lennertz and Benjamin Nota and Abdenur, {Jose E.} and David Coman and Das, {Anibh Martin} and Areeg El-Gharbawy and Nuoffer, {Jean Marc} and Branka Polic and Ren{\'e} Santer and Natalie Weinhold and Britton Zuccarelli and Ferdinando Palmieri and Luigi Palmieri and Salomons, {Gajja S.}",
year = "2018",
month = "3",
day = "1",
doi = "10.1007/s10545-017-0106-7",
language = "English",
volume = "41",
pages = "169--180",
journal = "Journal of Inherited Metabolic Disease",
issn = "0141-8955",
publisher = "Springer Netherlands",
number = "2",

}

Pop, A, Williams, M, Struys, EA, Monné, M, Jansen, EEW, de Grassi, A, Kanhai, WA, Scarcia, P, Ojeda, MRF, Porcelli, V, van Dooren, SJM, Lennertz, P, Nota, B, Abdenur, JE, Coman, D, Das, AM, El-Gharbawy, A, Nuoffer, JM, Polic, B, Santer, R, Weinhold, N, Zuccarelli, B, Palmieri, F, Palmieri, L & Salomons, GS 2018, 'An overview of combined D-2- and L-2-hydroxyglutaric aciduria: functional analysis of CIC variants' Journal of Inherited Metabolic Disease, vol. 41, no. 2, pp. 169-180. https://doi.org/10.1007/s10545-017-0106-7

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; Salomons, Gajja S.

In: Journal of Inherited Metabolic Disease, Vol. 41, No. 2, 01.03.2018, p. 169-180.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - An overview of combined D-2- and L-2-hydroxyglutaric aciduria

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 - http://www.scopus.com/inward/record.url?scp=85038021420&partnerID=8YFLogxK

U2 - 10.1007/s10545-017-0106-7

DO - 10.1007/s10545-017-0106-7

M3 - Article

VL - 41

SP - 169

EP - 180

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

SN - 0141-8955

IS - 2

ER -