Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency
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Curated by eLife
eLife assessment
This paper is a first report of a human subject with an MCAT mutation showing reduced mitochondrial activity, but without defining the molecular mechanism connecting the loss of MCAT activity to mitochondrial dysfunction. It adds to the important field of mitochondrial disease genes and how they impact human physiology.
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Abstract
Malonyl-CoA-acyl carrier protein transacylase (MCAT) is an enzyme involved in mitochondrial fatty acid synthesis (mtFAS) and catalyzes the transfer of the malonyl moiety of malonyl-CoA to the mitochondrial acyl carrier protein (ACP). Previously, we showed that loss-of-function of mtFAS genes, including Mcat , is associated with severe loss of electron transport chain (ETC) complexes in mouse immortalized skeletal myoblasts (Nowinski et al., 2020). Here, we report a proband presenting with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Using whole exome sequencing, we identified biallelic variants in MCAT . Protein levels for NDUFB8 and COXII, subunits of complex I and IV respectively, were markedly reduced in lymphoblasts and fibroblasts, as well as SDHB for complex II in fibroblasts. ETC enzyme activities were decreased in parallel. Re-expression of wild-type MCAT rescued the phenotype in patient fibroblasts. This is the first report of a patient with MCAT pathogenic variants and combined oxidative phosphorylation deficiency.
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eLife assessment
This paper is a first report of a human subject with an MCAT mutation showing reduced mitochondrial activity, but without defining the molecular mechanism connecting the loss of MCAT activity to mitochondrial dysfunction. It adds to the important field of mitochondrial disease genes and how they impact human physiology.
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Reviewer #1 (Public Review):
The manuscript by Webb et al., describes a proband with biallelic variants in the MCAT gene. The proband presents with hypotonia, failure to thrive, nystagmus, and abnormal brain MRI findings. Subsequent studies in isolated lymphoblasts and fibroblast samples from the proband unveil combined OXPHOS deficiency. Although the manuscript is of interest and adds translational impact to the previous work of the authors, a few issues remain unresolved. The study would benefit from additional functional tests of the variant MCAT allele.
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Reviewer #2 (Public Review):
This manuscript describes the first human subject with a demonstrated recessive pathogenic variant of MCAT. Analysis of cells from this subject in general showed similar abnormalities as previously demonstrated for MCAT deficiency in the mouse. This includes combined oxidative phosphorylation deficiency. The hypothesis that MCAT deficiency causes lowering of co-factor lipoate was tested, as PDH and other enzymes require this for function. However, no evidence for this concept was observed.
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