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Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria


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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Figure 1: Alignment of the motif regions in ACSF3 orthologs and the malonyl-CoA synthetase enzymes in bacteria.
Figure 2: MMA production by CMAMMA fibroblasts and lentiviral complementation with ACSF3.
Figure 3: ACSF3 mitochondrial localization.

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NCBI Reference Sequence


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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.

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J.C.S. and L.G.B. developed the exome sequencing protocol. J.L.S., I.M., J.C.S., L.G.B. and C.P.V. designed the clinical research studies. The NIH Intramural Sequencing Center Group (N.I.S.C.G.) performed exome sequencing. J.J.J., J.L.S., I.M., R.J.C., L.G.B. and C.P.V. performed bioinformatic analyses. J.J.J. and C.K. performed mutational analysis and genotyping. R.J.C., N.C.-C., S.D.C. and J.R.S. performed cell culture studies and protein blot analyses. R.J.C. created viral vectors and performed cellular complementation studies. J.L.S., M.H. and H.M.D. performed immunofluorescence experiments. J.L.S., J.R.S. and I.M. performed enzymatic assays. J.L.S., I.M., N.S.H., K.O., J.C.S., B.A.B., S.A.B., P.M.J., N.L.C., P.d.L., V.V., M.D.G., W.L.N., L.G.B. and C.P.V. contributed to clinical evaluations and the delineation of the subject phenotypes. D.K.G. performed organic acid measurements. J.L.S., J.J.J., L.G.B. and C.P.V. prepared the manuscript. L.G.B. and C.P.V. conceived of and supervised the study.

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Correspondence to Leslie G Biesecker.

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The authors declare no competing financial interests.

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NIH Intramural Sequencing Center Group

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Supplementary Figures 1–4 and Supplementary Tables 1–3. (PDF 2074 kb)

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Sloan, J., Johnston, J., Manoli, I. et al. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet 43, 883–886 (2011).

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