Quantification of various APP-mRNA isoforms and epistasis in Lesch-Nyhan disease

Systematic metabolic analysis of potential target, therapeutic drug, diagnostic method and animal model applicability in three neurodegenerative diseases

“…GOT1 encodes glutamic oxaloacetic transaminase in the cytoplasm, and downregulated GOT1 was found both in the elderly population and AD patients [33]. HPRT1 encodes hypoxanthine phosphoribosyltransferase 1, and mutated HPRT1 affects amyloid precursor protein (APP) gene expression in AD and amyotrophic lateral sclerosis (ALS) [34]. MAP2K1 regulates a wide variety of extraand intracellular signals.…”

Potential molecular link between the β-amyloid precursor protein (APP) and hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme in Lesch-Nyhan disease and cancer

“…The results indicated, for the first time, a role for epistasis between mutated HPRT1 and APP genes affecting the regulation of alternative APP pre-mRNA splicing in which APP-mRNA isoform of 624 bp, with a deletion starting after 49 bp of the 5′ end of exon 3 followed by a complete deletion of exons 4–15, mutations in exon 1: c.22C > T, p.L8F, and exon 3: c.269A > G, p.Q90R encoding APP 207 isoform was the most abundant one in most of the LND patients. This APP 207 isoform would be responsible for the neurobehavioral syndrome observed in these patients [10] . Furthermore, there were also some reported cases of LND/LNVs developing thrombosis [11] – [13] while APP is an important regulator of vein thrombosis and controls coagulation and neutrophil extracellular traps (NETs) formation via the Kunitz-type serine protease inhibitor (KPI)-containing the α soluble fragment of APP (APPsα fragment) that were demonstrated in vitro to be effective inhibitors of the coagulation FXa, FIXa, FXIa, and FVIIa:tissue factor complex [14] .…”

Epigenetics in Rare Diseases

“…Results of quantification of various APP-mRNA isoforms indicated an epistasis (gene-gene interactions) between mutated Hypoxanthine Phosphoribosyl Transferase 1 (HPRT1) and APP genes. APP-mRNA isoform of 624 bp, with deletion starting after 49 bp of the 5' end of exon 3 followed by a complete deletion of exons 4-15, mutations in exon 1: c.22C>T, p.L18F, and exon 3: c.269A>G, p.Q90R encoding APP 207 isoform, was the most abundant one in most of the LND patients and would be responsible for the neurobehavioral syndrome in these patients [28]. Interestingly, this APP 207 isoform was also the most abundant one found in a neurodevelopmental disorder resulting from a nonsense mutation in the Ox-2 antigen domain of the APP gene [29].…”