This report describes combined D-2- and L-2-hydroxyglutaric aciduria (D2L2AD); D2L2AD exhibit autosomal recessive inheritance. The human gene implicated in this disease is SLC25A1, a nuclear-encoded mitochondrial solute carrier protein known to transport citrate. There is a single orthologous gene in Drosophila, sea, for which RNAi-targeting constructs, alleles caused by insertional mutagenesis, and a loss-of-function allele caused by imprecise excision of a TE insertion have been generated. SLC25A1 may also be associated with a recessive form of congenital myasthenic syndrome (MIM:618197, 1 family).
The human SLC25A1 gene has not been introduced into flies. The human SLC25A1 gene is within the deletion associated with DiGeorge syndrome (also called 22q11.2 deletion syndrome; MIM:188400).
Animals homozygous for a loss-of-function allele of Dmel\sea die before adulthood; homozygous larvae have been used to characterize associated metabolic changes and to elucidate the role of a mitochondrial citrate transporter in the regulation of 2-hydroxyglutaric acid. In earlier work, it has been shown that sea mutant larval brain neuroblasts show defects in mitosis, with a high frequency of chromosome breaks. It is hypothesized that loss-of-function alleles of sea result in reduction of the efflux of citrate from mitochondria to cytosol, causing a global reduction of histone acetylation, which leads to high levels of chromosomal breakage.
Hemideficiency of Dmel\sea affects synapse morphology, neurotransmission, plasticity, and sleep patterns. Similar phenotypes are observed for animals hemizygous for a second Drosophila mitochondrial solute transporter (sesB; see FBhh0000372). It is postulated that this may extend more generally -- that synapse development is exquisitely sensitive to impairment of mitochondrial function, including reduced levels of mitochondrial solute transporters.
[updated Feb. 2020 by FlyBase; FBrf0222196]
[COMBINED D-2- AND L-2-HYDROXYGLUTARIC ACIDURIA; D2L2AD](https://omim.org/entry/615182)
[SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, CITRATE TRANSPORTER), MEMBER 1; SLC25A1](https://omim.org/entry/190315)
'Aciduria' refers to abnormally high levels of acid in the urine.
Combined D-2- and L-2-hydroxyglutaric aciduria (D-2-HG and L-2-HG) is an autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death (summary by Muntau et al., 2000; pubmed:10963100). [from MIM:615182; 2019.01.08]
Combined D-2- and L-2-hydroxyglutaric aciduria is caused by homozygous or compound heterozygous mutation in the SLC25A1 gene. [from MIM:615182; 2019.01.08]
Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts (summary by Muntau et al., 2000; pubmed:10963100). [from MIM:615182; 2019.01.08]
SLC25A1 encodes a member of a nuclear-encoded mitochondrial carrier subfamily of solute carrier proteins; it translocates small metabolites across the mitochondrial membrane. It is known to transport citrate and was originally designated 'mitochondrial citrate transporter' or 'citrate transport protein' (CTP). [Gene Cards; SLC25A1; 2019.01.08]
One to one: 1 human to 1 Drosophila
High-scoring ortholog of human SLC25A1 (1 Drosophila to 1 human). Dmel\sea shares 64% identity and 77% similarity with the human gene.
