title: Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter.
abstract: BACKGROUND
  Agenesis of corpus callosum has been associated with several defects of the mitochondrial respiratory chain and the citric acid cycle. We now report the results of the biochemical and molecular studies of a patient with severe neurodevelopmental disease manifesting by agenesis of corpus callosum and optic nerve hypoplasia.
  
  
  RESULTS
  A mitochondrial disease was suspected in this patient based on the prominent excretion of 2-hydroxyglutaric acid and Krebs cycle intermediates in urine and the finding of increased reactive oxygen species content and decreased mitochondrial membrane potential in her fibroblasts. Whole exome sequencing disclosed compound heterozygosity for two pathogenic variants in the SLC25A1 gene, encoding the mitochondrial citrate transporter. These variants, G130D and R282H, segregated in the family and were extremely rare in controls. The mutated residues were highly conserved throughout evolution and in silico modeling investigations indicated that the mutations would have a deleterious effect on protein function, affecting either substrate binding to the transporter or its translocation mechanism. These predictions were validated by the observation that a yeast strain harbouring the mutations at equivalent positions in the orthologous protein exhibited a growth defect under stress conditions and by the loss of activity of citrate transport by the mutated proteins reconstituted into liposomes.
  
  
  CONCLUSIONS
  We report for the first time a patient with a mitochondrial citrate carrier deficiency. Our data support a role for citric acid cycle defects in agenesis of corpus callosum as already reported in patients with aconitase or fumarate hydratase deficiency.
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
authors: Simon
authors: S
authors: Edvardson
authors: Vito
authors: V
authors: Porcelli
authors: Chaim
authors: C
authors: Jalas
authors: Devorah
authors: D
authors: Soiferman
authors: Yuval
authors: Y
authors: Kellner
authors: Avraham
authors: A
authors: Shaag
authors: Stanley H
authors: SH
authors: Korman
authors: Ciro Leonardo
authors: CL
authors: Pierri
authors: Pasquale
authors: P
authors: Scarcia
authors: Nitay D
authors: ND
authors: Fraenkel
authors: Reeval
authors: R
authors: Segel
authors: Abraham
authors: A
authors: Schechter
authors: Ayala
authors: A
authors: Frumkin
authors: Ophry
authors: O
authors: Pines
authors: Ann
authors: A
authors: Saada
authors: Luigi
authors: L
authors: Palmieri
authors: Orly
authors: O
authors: Elpeleg
mesh_terms: D000293:Adolescent; D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000473:pathology; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology*; D027361:Organic Anion Transporters
chemical_list: D027321:Anion Transport Proteins; D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D027361:Organic Anion Transporters; C532592:Slc25a1 protein, human; C020723:citrate-binding transport protein