Dataset Information

Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

ABSTRACT: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.

SUBMITTER: van Es MA

PROVIDER: S-EPMC5560057 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

van Es Michael A MA Schelhaas Helenius J HJ van Vught Paul W J PW Ticozzi Nicola N Andersen Peter M PM Groen Ewout J N EJ Schulte Claudia C Blauw Hylke M HM Koppers Max M Diekstra Frank P FP Fumoto Katsumi K LeClerc Ashley Lyn AL Keagle Pamela P Bloem Bastiaan R BR Scheffer Hans H van Nuenen Bart F L BF van Blitterswijk Marka M van Rheenen Wouter W Wills Anne-Marie AM Lowe Patrick P PP Hu Guo-fu GF Yu Wenhao W Kishikawa Hiroko H Wu David D Folkerth Rebecca D RD Mariani Claudio C Goldwurm Stefano S Pezzoli Gianni G Van Damme Philip P Lemmens Robin R Dahlberg Caroline C Birve Anna A Fernández-Santiago Rubén R Waibel Stefan S Klein Christine C Weber Markus M van der Kooi Anneke J AJ de Visser Marianne M Verbaan Dagmar D van Hilten Jacobus J JJ Heutink Peter P Hennekam Eric A M EA Cuppen Edwin E Berg Daniela D Brown Robert H RH Silani Vincenzo V Gasser Thomas T Ludolph Albert C AC Robberecht Wim W Ophoff Roel A RA Veldink Jan H JH Pasterkamp R Jeroen RJ de Bakker Paul I W PI Landers John E JE van de Warrenburg Bart P BP van den Berg Leonard H LH

Annals of neurology 20111201 6

<h4>Objective</h4>Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ...[more]

PMID: 22190368

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Project description:BACKGROUND: Mutations in the coding region of angiogenin (ANG) gene have been found in patients suffering from Amyotrophic Lateral Sclerosis (ALS). Neurodegeneration results from the loss of angiogenic ability of ANG (protein coded by ANG). In this work, we performed extensive molecular dynamics (MD) simulations of wild-type ANG and disease associated ANG variants to elucidate the mechanism behind the loss of ribonucleolytic activity and nuclear translocation activity, functions needed for angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: MD simulations were carried out to study the structural and dynamic differences in the catalytic site and nuclear localization signal residues between WT-ANG (Wild-type ANG) and six mutants. Variants K17I, S28N, P112L and V113I have confirmed association with ALS, while T195C and A238G single nucleotide polymorphisms (SNPs) encoding L35P and K60E mutants respectively, have not been associated with ALS. Our results show that loss of ribonucleolytic activity in K17I is caused by conformational switching of the catalytic residue His114 by 99°. The loss of nuclear translocation activity of S28N and P112L is caused by changes in the folding of the residues (31)RRR(33) that result in the reduction in solvent accessible surface area (SASA). Consequently, we predict that V113I will exhibit loss of angiogenic properties by loss of nuclear translocation activity and L35P by loss of both ribonucleolytic activity and nuclear translocation activity. No functional loss was inferred for K60E. The MD simulation results were supported by hydrogen bond interaction analyses and molecular docking studies. CONCLUSIONS/SIGNIFICANCE: Conformational switching of catalytic residue His114 seems to be the mechanism causing loss of ribonucleolytic activity and reduction in SASA of nuclear localization signal residues (31)RRR(33) results in loss of nuclear translocation activity in ANG mutants. Therefore, we predict that L35P mutant, would exhibit loss of angiogenic functions, and hence would correlate with ALS while K60E would not show any loss.

Dataset Information

Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

Publications

Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

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