This report describes mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria), which shows autosomal recessive inheritance. The human gene implicated in this disease is succinate-CoA ligase alpha subunit (SUCLG1).
There is a high-ranking ortholog of SUCLG1 in Drosophila, Scsα1, along with a moderately-ranking ortholog, Scsα2, which is expressed almost exclusively in testis. Multiple alleles have been generated for Scsα1, including RNAi targeting constructs, hypomorphic and amorphic alleles, and insertion lines.
The human gene SUCLG1 has not been introduced into flies.
Drosophila mutants with a CRISPR-genereated knockout of Scsα1 have elevated levels of succinyl-CoA, a substrate of Scsα1, as well as other glycolysis and TCA cycle metabolites. Mutants also showed developmental delay, decreased locomotor activity, and reduced survival under starvation conditions.
[updated May 2019 by FlyBase; FBrf0222196]
Mitochondrial DNA (mtDNA) depletion syndrome (MDS) is a clinically heterogeneous group of mitochondrial disorders characterized by a reduction of the mtDNA copy number in affected tissues without mutations or rearrangements in the mtDNA. MDS is phenotypically heterogeneous, and can affect a specific organ or a combination of organs, with the main presentations described being either hepatocerebral (i.e. hepatic dysfunction, psychomotor delay), myopathic (i.e. hypotonia, muscle weakness, bulbar weakness), encephalomyopathic (i.e. hypotonia, muscle weakness, psychomotor delay) or neurogastrointestinal (i.e gastrointestinal dysmotility, peripheral neuropathy). [http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=35698.0 2016.11.23]
[MITOCHONDRIAL DNA DEPLETION SYNDROME 9 (ENCEPHALOMYOPATHIC TYPE WITH METHYLMALONIC ACIDURIA); MTDPS9](https://omim.org/entry/245400)
[SUCCINATE-CoA LIGASE, GDP/ADP-FORMING, SUBUNIT ALPHA; SUCLG1](https://omim.org/entry/611224)
Three patients with SUCLG1 mutations had an extremely severe phenotype with antenatal manifestations of the disorder, severe acidosis with lactic aciduria in the first day of life and death within 2-4 days. Liver histology in a patient with a SUCLG1 mutation showed steatosis. Muscle histology showed severe lipid accumulation. (adapted from Ostergaard 2008, pubmed:18392745)
Mitochondrial DNA depletion syndrome 9 is a severe autosomal recessive disorder characterized by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. Some patients die in early infancy (summary by Rouzier et al., 2010, pubmed:20693550). [from MIM:245400, 2019.05.17]
SUCLG1 was identified as a likely candidate gene after performing a genomewide search for homozygosity in two siblings from a small consanguineous family with three affected children. (adapted from Ostergaard 2008, pubmed:18392745)
In a consanguineous family with a history of mitochondrial DNA depletion syndrome 9, DNA sequencing revealed a homozygous 2-bp deletion in SUCLG1, a gene that encodes the alpha subunit of the Krebs cycle enzyme succinate-coenzyme A ligase (SUCL; Ostergaard et al. 2007, pubmed:17668387). The mtDNA depletion was thought to be explained by decreased mitochondrial nucleoside diphosphate kinase (NDPK) activity resulting from the inability of NDPK to form a complex with SUCL. [from MIM:245400, 2019.05.17]
Analysis of mitochondrial protein in muscle and liver by blue native PAGE (BN-PAGE) showed a decreased amount of fully assembled complexes I, III, and IV. The amount of complex V was normal in muscle and increased in liver. The amount of complex II, which is encoded only by nuclear genes, was normal. (Ostergaard et al. 2007, pubmed:17668387)
In humans: Succinyl-CoA synthetase/ligase (SCS) is a mitochondrial enzyme that catalyzes the reversible process from succinyl-CoA to succinate and free coenzyme A in TCA cycle. SCS is a heterodimeric enzyme composed of an invariant α subunit encoded by SUCLG1 and a β subunit that determines the enzyme's nucleotide specificity: the GTP-specific β subunit encoded by SUCLG2 and the ATP-specific β subunit encoded by SUCLA2. (Quan et al. 2017, FBrf0234532.)
One human gene to many Drosophila genes; 1 human to 2 Drosophila.
High-ranking ortholog of SUCLG1.
