Exome sequencing identifies ACSF3 as the cause of Combined Malonic and Methylmalonic Aciduria

Genetics and Molecular Biology Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Nature Genetics (Impact Factor: 29.35). 08/2011; 43(9):883-6. DOI: 10.1038/ng.908
Source: PubMed


We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in ∼1,000 control individuals, predicting a CMAMMA population incidence of ∼1:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders.

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    • "Deficiency of ACSF3, encoding an acyl-CoA synthetase, results in combined malonic acid/methylmalonic acid excretion in urine (CMAMMA; MIM614265), but there was neither LA synthesis defect, nor lactic acidosis, nor glycine elevation noted (Alfares et al 2011; Sloan et al 2011). Even though this enzymatic step seems to play a role in mitochondrial fatty acid synthesis, there is probably a backup for malonyl-CoA synthesis in mitochondria (Witkowski et al 2011). "
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