title: Epigenetic regulation in amyloid precursor protein and the Lesch-Nyhan syndrome.
abstract: Lesch-Nyhan syndrome (LNS) is a neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT) is defective. A major unsolved question is how the loss of HPRT enzyme function affects the brain to cause the neurobehavioural syndrome in LNS and its attenuated variants (LNVs). To address this issue, a search for a link between LNS and the amyloid precursor protein (APP) is developed. Here, I identified, for the first time in fibroblasts from normal subjects as well as from LNS and LNV patients: (a) several APP-mRNA isoforms encoding divers APP protein isoforms ranging from 120 to 770 amino acids (with or without mutations and/or deletions) accounted for epigenetic mechanisms in the regulation of alternative APP pre-mRNA splicing and (b) five novel independent polymorphisms in the APP promoter: -956A>G, -1023T>C, -1161A>G, -2224G>A, -2335C>T relative to the transcription start site. A role for epistasis between mutated HPRT and APP genes affecting the regulation of alternative APP pre-mRNA splicing in LNS is suggested. An accurate quantification of various APP isoforms in brain tissues for detection of initial pathological changes or pathology development is needed. My findings may provide new directions not only for investigating the role of APP in neuropathology associated with HPRT-deficiency in LNS but also for the research in neurodevelopmental and neurodegenerative disorders by which various APP isoforms involved in the pathogenesis of the diseases such as Alzheimer's disease.
authors.affiliation: Department of Medicine, Biochemical Genetics and Metabolism, The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California, San Diego, Building CTF, Room C-103, 214 Dickinson Street, San Diego, CA 92103-8467, USA; Department of Pediatrics, University of California, San Diego, School of Medicine, San Diego, La Jolla, CA 92093, USA. Electronic address: kvn006@ucsd.edu.
authors.forename: Khue Vu
authors.initials: KV
authors.lastname: Nguyen
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007926:Lesch-Nyhan Syndrome / Q000201:enzymology / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D012322:RNA Precursors / Q000235:genetics; D012326:RNA Splicing
chemical_list: D016564:Amyloid beta-Protein Precursor; D020033:Protein Isoforms; D012322:RNA Precursors; D007041:Hypoxanthine Phosphoribosyltransferase
keywords: Alzheimer’s disease; Amyloid precursor protein; Epigenetics; Epistasis; HPRT; Lesch-Nyhan syndrome