Sarah K Tschirner1, Heike Bähre2, Alexander Kaever3, Erich H Schneider4, Roland Seifert5, Volkhard Kaever6. 1. Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: tschirner.sarah@mh-hannover.de. 2. Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; Research Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: baehre.heike@mh-hannover.de. 3. Department of Bioinformatics, Institute of Microbiology and Genetics, Georg-August-University Göttingen, Goldschmidtstr. 1, D-37077 Göttingen, Germany. Electronic address: alex@gobics.de. 4. Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: schneider.erich@mh-hannover.de. 5. Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: seifert.roland@mh-hannover.de. 6. Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany; Research Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: kaever.volkhard@mh-hannover.de.
Abstract
AIMS: Lesch-Nyhan disease (LND) is characterized by hyperuricemia as well as neurological and neuropsychiatric symptoms including repetitive self-injurious behavior. Symptoms are caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a result of a mutation on the X chromosome. To elucidate the pathophysiology of LND, we performed a metabolite screening for brain and serum extracts from HPRT knockout mice as an animal model for LND. MAIN METHODS: Analyses were performed by high performance liquid chromatography (HPLC)-coupled quadrupole time-of-flight mass spectrometry (QTOF-MS). KEY FINDINGS: In brain extracts, we found six metabolites with significantly different contents in wild-type and HPRT-deficient mice. Two compounds we could identify as 5-aminoimidazole-4-carboxamide ribotide (AICAR) and 1-methylimidazole-4-acetic acid (1-MI4AA). Whereas AICAR was accumulated in brains of HPRT knockout mice, 1-MI4AA was decreased in these mice. SIGNIFICANCE: Both metabolites play a role in histidine metabolism and, as a consequence, histamine metabolism. AICAR, in addition, is part of the purine metabolism. Our findings may help to better understand the mechanisms leading to the behavioral phenotype of LND.
AIMS: Lesch-Nyhan disease (LND) is characterized by hyperuricemia as well as neurological and neuropsychiatric symptoms including repetitive self-injurious behavior. Symptoms are caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a result of a mutation on the X chromosome. To elucidate the pathophysiology of LND, we performed a metabolite screening for brain and serum extracts from HPRT knockout mice as an animal model for LND. MAIN METHODS: Analyses were performed by high performance liquid chromatography (HPLC)-coupled quadrupole time-of-flight mass spectrometry (QTOF-MS). KEY FINDINGS: In brain extracts, we found six metabolites with significantly different contents in wild-type and HPRT-deficientmice. Two compounds we could identify as 5-aminoimidazole-4-carboxamide ribotide (AICAR) and 1-methylimidazole-4-acetic acid (1-MI4AA). Whereas AICAR was accumulated in brains of HPRT knockout mice, 1-MI4AA was decreased in these mice. SIGNIFICANCE: Both metabolites play a role in histidine metabolism and, as a consequence, histamine metabolism. AICAR, in addition, is part of the purine metabolism. Our findings may help to better understand the mechanisms leading to the behavioral phenotype of LND.
Authors: J E Visser; S M Kolk; J S Witteveen; S R Loopstok; L Luque Ballesteros; A Boonstra; N H M van Bakel; W H P van Boekel; G J M Martens Journal: Cell Mol Life Sci Date: 2022-06-04 Impact factor: 9.207
Authors: Lucie Mádrová; Matyáš Krijt; Veronika Barešová; Jan Václavík; David Friedecký; Dana Dobešová; Olga Součková; Václava Škopová; Tomáš Adam; Marie Zikánová Journal: PLoS One Date: 2018-12-10 Impact factor: 3.240
Authors: José M López; Esther L Outtrim; Rong Fu; Diane J Sutcliffe; Rosa J Torres; H A Jinnah Journal: Proc Natl Acad Sci U S A Date: 2020-05-19 Impact factor: 11.205