TY - JOUR
T1 - Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria
AU - Sloan, Jennifer L.
AU - Johnston, Jennifer J.
AU - Manoli, Irini
AU - Chandler, Randy J.
AU - Krause, Caitlin
AU - Carrillo-Carrasco, Nuria
AU - Chandrasekaran, Suma D.
AU - Sysol, Justin R.
AU - O'Brien, Kevin
AU - Hauser, Natalie S.
AU - Sapp, Julie C.
AU - Dorward, Heidi M.
AU - Huizing, Marjan
AU - Barshop, Bruce A.
AU - Berry, Susan A.
AU - James, Philip M.
AU - Champaigne, Neena L.
AU - De Lonlay, Pascale
AU - Valayannopoulos, Vassilli
AU - Geschwind, Michael D.
AU - Gavrilov, Dimitar K.
AU - Nyhan, William L.
AU - Biesecker, Leslie G.
AU - Venditti, Charles P.
N1 - Funding Information:
We thank the subjects and families for participating, E. Ostrander for the gift of unrelated Labrador DNA samples, K.M. Gibson and R. Wander for performing the malonyl-CoA decarboxylase assay on fibroblasts from subjects 2 and 9, J. Teer for bioinformatics assistance, S. Suchy for subject referral, M. Podell and W. Gahl for helpful discussions, R. Fisher, I. Bernardini, A. Gropman, L. Hecht, F. Facio, C. Gitiaux, C. Ottolenghi, D. Rabier and G. Touati for laboratory assistance and clinical care, and M. Oglesbee and A. Genders for searching for dogs related to the affected Labrador retriever. J.L.S., J.J.J., I.M., R.J.C., N.C.-C., S.D.C., J.R.S., H.M.D., M.H., K.O., N.S.H., J.C.S., C.K., L.G.B. and C.P.V. were supported by the Intramural Research Program of the NHGRI, NIH. M.D.G. was supported by NIA K23 AG021989 and R01-AG031189.
PY - 2011/9
Y1 - 2011/9
N2 - 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 1/41,000 control individuals, predicting a CMAMMA population incidence of 1/41:30,000. 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.
AB - 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 1/41,000 control individuals, predicting a CMAMMA population incidence of 1/41:30,000. 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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U2 - 10.1038/ng.908
DO - 10.1038/ng.908
M3 - Article
C2 - 21841779
AN - SCOPUS:80052269204
SN - 1061-4036
VL - 43
SP - 883
EP - 886
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -