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Thiamine Pyrophosphokinase Deficiency in Encephalopathic Children with Defects in the Pyruvate Oxidation Pathway  Johannes A. Mayr, Peter Freisinger,

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Presentation on theme: "Thiamine Pyrophosphokinase Deficiency in Encephalopathic Children with Defects in the Pyruvate Oxidation Pathway  Johannes A. Mayr, Peter Freisinger,"— Presentation transcript:

1 Thiamine Pyrophosphokinase Deficiency in Encephalopathic Children with Defects in the Pyruvate Oxidation Pathway  Johannes A. Mayr, Peter Freisinger, Kurt Schlachter, Boris Rolinski, Franz A. Zimmermann, Thomas Scheffner, Tobias B. Haack, Johannes Koch, Uwe Ahting, Holger Prokisch, Wolfgang Sperl  The American Journal of Human Genetics  Volume 89, Issue 6, Pages (December 2011) DOI: /j.ajhg Copyright © 2011 The American Society of Human Genetics Terms and Conditions

2 Figure 1 Thiamine Metabolism in Mammalian Cells
The following abbreviations are used: TPP, thiamine pyrophosphate; PDHC, pyruvate dehydrogenase complex; α-KGDH, α-ketoglutarate dehydrogenase; BCKDH, branched chain α-keto acid dehydrogenase. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

3 Figure 2 Pedigrees of the Five Affected Individuals from Three Families The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Investigations of Cofactor Dependency of Pyruvate Dehydrogenase Complex Activity Pyruvate dehydrogenase complex was measured in the in the absence of thiamine pyrophosphate and showed a decrease in the affected individuals compared to controls (A). An even more pronounced decrease was found in the ratio of PDHC activities under TPP-unsupplemented versus TPP-supplemented (0.8 mmol/l) assay conditions (B). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Sequence Analysis of TPK1
Sequence analysis revealed compound heterozygous mutations c.[148A>C]+[501+4A>T] p.[Asn50His]+[Val119_Pro167del] in the individuals P1 and P2 (Figure 2) in TPK1 (RefSeq NM_ ). In the individuals P3 and P4 a homozygous mutation c.119T>C p.Leu40Pro was found. In the individual P5 compound heterozygous mutations c.[179_182delGAGA]+[656A>G] p.[Arg60LysfsX52]+[Asn219Ser] were found. The expression of the missense mutations is shown in the cDNA of the affected individuals. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

6 Figure 5 Phylogenetic Conservation of the Identified Thiamine Phyrophosphokinase Mutations Alignment by ClustalW24 shows phylogenetic conservation of missense mutations found in the thiamine pyrophosphokinase in the affected individuals (P1–P5, cf. Figure 2). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

7 Figure 6 Immunoblot Analysis of Muscle Extracts
A decrease in the amount of the active isoform a (27.3 kDa) was found in all affected individuals with a TPK antibody (A). An antibody against glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as loading control for cytosolic protein (B). The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

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