A Novel Regulatory Defect in the Branched-Chain α-Keto Acid Dehydrogenase Complex Due to a Mutation in thePPM1KGene Causes a Mild Variant Phenotype of Maple Syrup Urine Disease

Oyarzábal, Alfonso; Martínez‐Pardo, Mercedes; Merinero, Begoña; Navarrete, Rosa; Desviat, Lourdes R.; Ugarte, Magdalena; Rodríguez‐Pombo, Pilar

doi:10.1002/humu.22242

Cited by 75 publications

(79 citation statements)

References 29 publications

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“…This reaction is the irreversible and rate-limiting step in BCAA metabolism, catalysed by the mitochondrial BCKD complex [55]. The pattern of association observed in this study mirrors that observed in maple syrup urine disease (MSUD), an inborn error of metabolism caused by rare loss-of-function mutations in genes encoding components of the BCKD complex [55] or its regulatory phosphatase [56]. In our GWAS of BCAA levels, the strongest association signal was located 21 kb upstream of the PPM1K gene, which encodes the mitochondrial phosphatase that activates BCKD [49–51].…”

Section: Discussionsupporting

confidence: 60%

“…In our GWAS of BCAA levels, the strongest association signal was located 21 kb upstream of the PPM1K gene, which encodes the mitochondrial phosphatase that activates BCKD [49–51]. Loss-of-function mutations of PPM1K in humans [56] or the knock-out of its ortholog Ppm1k in mice models [35] results in impaired BCKD activity and high levels of BCAAs and branched-chain alpha-ketoacids, a pattern that resembles that observed for common PPM1K genetic variants in our study. Therefore, it is plausible that the genetic variants identified in this study act by impairing the catabolism of BCAAs, hence leading to higher circulating levels of these amino acids.…”

Section: Discussionmentioning

confidence: 99%

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Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

et al. 2016

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BackgroundHigher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question.Methods and FindingsGenome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10−8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10−25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26–1.65, p = 9.5 × 10−8) for isoleucine, 1.85 (95% CI 1.41–2.42, p = 7.3 × 10−6) for leucine, and 1.54 (95% CI 1.28–1.84, p = 4.2 × 10−6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes.ConclusionsEvidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

et al. 2016

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“…Insulin is the chief regulator of amino acid metabolism and changes in fasting BCAA levels may be regulated by the effect of insulin on the rate of appearance and clearance of BCAA together with a decreased activity of catabolic enzymes [2]. Loss-of-function mutations in PPM1K in humans [21], and disruption of key BCAA metabolism in obese mice and Zucker rats, exhibit a reduced expression of the mitochondrial isoform of branched chain-amino-acid transaminase (BCAT2; which catalyses the first and reversible step in BCAA catabolism), and mitochondrial branched chain α-keto acid dehydrogenase (BCKD) complex E1-α (which catalyses the rate-controlling and the first irreversible step), leading to increased plasma BCAA levels [22,23]. A decreased BCAA metabolism in fat tissue may contribute to higher BCAA levels in individuals with insulin-resistant obesity [2,[22][23][24].…”

Section: Discussionmentioning

confidence: 99%

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels

et al. 2017

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Aims/hypothesis Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with circulating BCAA levels and insulin resistance as instrumental variables. Methods We measured circulating BCAA levels in blood plasma by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort. We complemented our analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 46,186) and from a GWAS of serum BCAA levels (n = 24,925). We used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels. Conclusions/interpretation Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance while increased insulin resistance drives higher circulating fasting BCAA levels. Results

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“…Protein phosphatase 2C in mitochondria (PP2Cm) is a mitochondrial matrix-targeted serine/threonine protein phosphatase encoded by the gene PPM1K [1,2] . It is a member of the protein phosphatase 2C family and is highly conserved among vertebrates.…”

Section: Introductionmentioning

confidence: 99%

Regulation of PP2Cm expression by miRNA-204/211 and miRNA-22 in mouse and human cells

et al. 2015

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Aim:The mitochondrial targeted 2C-type serine/threonine protein phosphatase (PP2Cm) is encoded by the gene PPM1K and is highly conserved among vertebrates. PP2Cm plays a critical role in branched-chain amino acid catabolism and regulates cell survival. Its expression is dynamically regulated by the nutrient environment and pathological stresses. However, little is known about the molecular mechanism underlying the regulation of PPM1K gene expression. In this study, we aimed to reveal how PPM1K expression is affected by miRNA-mediated post-transcriptional regulation. Methods: Computational analysis based on conserved miRNA binding motifs was applied to predict the candidate miRNAs that potentially affect PPM1K expression. Dual-luciferase reporter assay was performed to verify the miRNAs' binding sites in the PPM1K gene and their influence on PPM1K 3'UTR activity. We further over-expressed the mimics of these miRNAs in human and mouse cells to examine whether miRNAs affected the mRNA level of PPM1K. Results: Computational analysis identified numerous miRNAs potentially targeting PPM1K. Luciferase reporter assays demonstrated that the 3'UTR of PPM1K gene contained the recognition sites of miR-204 and miR-211. Overexpression of these miRNAs in human and mouse cells diminished the 3'UTR activity and the endogenous mRNA level of PPM1K. However, the miR-22 binding site was found only in human and not mouse PPM1K 3'UTR. Accordingly, PPM1K 3'UTR activity was suppressed by miR-22 overexpression in human but not mouse cells. Conclusion: These data suggest that different miRNAs contribute to the regulation of PP2Cm expression in a species-specific manner. miR-204 and miR-211 are efficient in both mouse and human cells, while miR-22 regulates PP2Cm expression only in human cells.

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A Novel Regulatory Defect in the Branched-Chain α-Keto Acid Dehydrogenase Complex Due to a Mutation in thePPM1KGene Causes a Mild Variant Phenotype of Maple Syrup Urine Disease

Cited by 75 publications

References 29 publications

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels

Regulation of PP2Cm expression by miRNA-204/211 and miRNA-22 in mouse and human cells

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