Autosomal-Dominant Striatal Degeneration Is Caused by a Mutation in the Phosphodiesterase 8B Gene Silke Appenzeller, Anja Schirmacher, Hartmut Halfter,

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Autosomal-Dominant Striatal Degeneration Is Caused by a Mutation in the Phosphodiesterase 8B Gene Silke Appenzeller, Anja Schirmacher, Hartmut Halfter, Sebastian Bäumer, Manuela Pendziwiat, Vincent Timmerman, Peter De Jonghe, Klára Fekete, Florian Stögbauer, Peter Lüdemann, Margret Hund, Elgar Susanne Quabius, E. Bernd Ringelstein, Gregor Kuhlenbäumer The American Journal of Human Genetics Volume 86, Issue 1, Pages 83-87 (January 2010) DOI: 10.1016/j.ajhg.2009.12.003 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 MRI Features and Pedigree of the ADSD Family (A) T2-weighted images of a healthy control (left) and ADSD patient III:5 (right; encircled are regions of pathologic signal increase). (B) Pedigree of the ADSD family. Clear symbols represent unaffected individuals. Filled symbols represent individuals with ADSD. Individuals were considered affected on the basis of the characteristic symmetric MRI abnormalities of the basal ganglia. The index patient (IV:2, arrow) is shown in Movie S1. Segregation analysis showed perfect cosegregation of the PDE8B mutation (c.94G>C+c.95delT) with ADSD. +/m denotes heterozygous mutation carriers; +/+ denotes individuals homozygous for the wild-type allele. The American Journal of Human Genetics 2010 86, 83-87DOI: (10.1016/j.ajhg.2009.12.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 ADSD Candidate Region, Genomic Organization of PDE8B, PDE8B Mutation Found in the ADSD Family, Structural and Functional Consequences for the Protein (A) The 3.25 Mb candidate region with locations of all 21 RefSeq annotated protein coding genes. (B) Genomic organization of the different PDE8B variants. The localization of the ADSD-causing mutation in exon 1 is indicated by an arrow. Accession numbers of PDE8B isoforms are given in Table S4. (C) Complex (c.94G>C+c.95delT) mutation found in the ADSD family. Shown is the reverse sequence. (D) Protein structure of PDE8B and position of the functional domains REC, PAS, and PDE in PDE8B isoform 1. (E) Structure of the truncated protein. The altered amino acid sequence starting at residue 32 is shaded. (F) Amino acid sequence of the truncated protein. Residues 1–31 (upper row, black) and altered residues 32–63 (lower row, red) are shown. (G) Effects of the PDE8B mutation on cAMP levels. All error bars indicate standard deviation (SD). Each sample was run in triplicate (n = 3) and the experiment was repeated three times. ∗ indicates a significant difference between wild-type and mutant (p < 0.05) and wild-type and empty vector (p < 0.01). The difference between mutant and empty vector was not significant. Luminescence (RLU) is inversely proportional to cAMP levels. High PDE8B activity results in low cAMP concentration, leading to high luminescence. The American Journal of Human Genetics 2010 86, 83-87DOI: (10.1016/j.ajhg.2009.12.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 3 Expression of PDE8B Relative quantification of PDE8B in various human tissues by real-time PCR and standard deviation. Quantification was performed with ACTB, GAPDH, and PPIA as reference genes. All error bars indicate SD. Each sample was run in triplicate (n = 3). The American Journal of Human Genetics 2010 86, 83-87DOI: (10.1016/j.ajhg.2009.12.003) Copyright © 2010 The American Society of Human Genetics Terms and Conditions