Functional Consequences of PRODH Missense Mutations

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Presentation transcript:

Functional Consequences of PRODH Missense Mutations Hans-Ulrich Bender, Shlomo Almashanu, Gary Steel, Chien-An Hu, Wei-Wen Lin, Alecia Willis, Ann Pulver, David Valle The American Journal of Human Genetics Volume 76, Issue 3, Pages 409-420 (March 2005) DOI: 10.1086/428142 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 Diagram of PRODH (upper panel) and ΨPRODH (lower panel). The exons, represented by the gray rectangles, are numbered and shown roughly to scale. The intronic sequence is represented by the black heavy line and is not to scale. The exonic location of the missense mutations, by exon, is shown above the rectangles. The translation start site in exon 2 is indicated by the right-angle arrow; the heavy dashed line below the rectangles in the upper panel indicates the ∼10-kb PRODH-specific PCR product. The deletion in ΨPRODH is indicated by the dashed lines in the lower panel. The American Journal of Human Genetics 2005 76, 409-420DOI: (10.1086/428142) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 Schematic representation of proline metabolic pathways. The rectangle represents a mitochondrion (see text for additional details). The American Journal of Human Genetics 2005 76, 409-420DOI: (10.1086/428142) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 3 Alignment of the predicted PRODH amino acid sequences from various eukaryotic species. Residues conserved across three or four of the sequences are indicated by a gray background, those conserved in all five eukaryotic examples by a black background. Also shown are the 40 residues of E. coli PutA669 that are within 5 Å of substrate and/or cofactor (Lee et al. 2003). These are spaced as they are in PutA669, but, for the sake of clarity, we have not shown the intervening residues. The shading scheme for the E. coli residues follows the convention for the eukaryotic sequences. The locations of the human missense mutations studied in this article are indicated at the top of the figure. The arrowhead indicates the predicted cleavage site for the mitochondrial targeting sequence. The overline indicates a possible leucine zipper motif. Hs=Homo sapiens, Mm=Mus musculus, Dm=Drosophila melanogaster, Ce=Caenorhabditis elegans, Sc=Saccharomyces cerevisiae, and Ec=E. coli. The American Journal of Human Genetics 2005 76, 409-420DOI: (10.1086/428142) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 4 Immunoblot analysis of POX and GFP in sonicates of cells transfected with the indicated recombinant pTracer construct. For each panel, POX is shown above, GFP below. Each lane contains 20 μg of crude cell sonicate. POX migrates as an ∼66-kDa protein. The American Journal of Human Genetics 2005 76, 409-420DOI: (10.1086/428142) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 5 Proline oxidase activity of PRODH alleles. For each transfected allele, the activity was normalized to transfection efficiency and was expressed as a percentage of the wild-type allele (see the “Material and Methods” section). The thin vertical lines indicate the range of mean activity measured in two-to-five independent transient transfection experiments. Bars without these vertical lines indicate the mean of a triplicate assay performed in one transfection experiment. For some alleles (L441P, R453C/T466M, and A472T), the value is from multiple experiments, but the variance is so narrow that it cannot be seen on this scale. The American Journal of Human Genetics 2005 76, 409-420DOI: (10.1086/428142) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 6 Structural models of the active site of human POX, as predicted from the solved structure of E. coli PutA669 (Lee et al. 2003). The location of residues altered in certain of the missense mutations is shown: A, T466M; B, Q521E; C, L441P. The white arrows indicate potential disruptive forces. The American Journal of Human Genetics 2005 76, 409-420DOI: (10.1086/428142) Copyright © 2005 The American Society of Human Genetics Terms and Conditions