title: Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria.
abstract: 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.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sloan
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.forename: Irini
authors.initials: I
authors.lastname: Manoli
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Chandler
authors.forename: Caitlin
authors.initials: C
authors.lastname: Krause
authors.forename: Nuria
authors.initials: N
authors.lastname: Carrillo-Carrasco
authors.forename: Suma D
authors.initials: SD
authors.lastname: Chandrasekaran
authors.forename: Justin R
authors.initials: JR
authors.lastname: Sysol
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Brien
authors.forename: Natalie S
authors.initials: NS
authors.lastname: Hauser
authors.forename: Julie C
authors.initials: JC
authors.lastname: Sapp
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Dorward
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Barshop
authors.forename: Susan A
authors.initials: SA
authors.lastname: Berry
authors.forename: Philip M
authors.initials: PM
authors.lastname: James
authors.forename: Neena L
authors.initials: NL
authors.lastname: Champaigne
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Vassilli
authors.initials: V
authors.lastname: Valayannopoulos
authors.forename: Michael D
authors.initials: MD
authors.lastname: Geschwind
authors.forename: Dimitar K
authors.initials: DK
authors.lastname: Gavrilov
authors.forename: William L
authors.initials: WL
authors.lastname: Nyhan
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Charles P
authors.initials: CP
authors.lastname: Venditti
mesh_terms: D000293:Adolescent; D000368:Aged; D000595:Amino Acid Sequence; D002262:Carboxy-Lyases / Q000172:deficiency / Q000235:genetics; D002675:Child, Preschool; D003066:Coenzyme A Ligases / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008316:Malonyl Coenzyme A; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008764:Methylmalonic Acid; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: D008316:Malonyl Coenzyme A; D008764:Methylmalonic Acid; D002262:Carboxy-Lyases; C561770:ACSF3 protein, human; D003066:Coenzyme A Ligases