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

Abstract

<abstract> <p>Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorders of purine metabolic in which the cytoplasmic enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. Despite having been characterized over 60 years ago, however, up to now, there is no satisfactory explanation of how deficits in enzyme HGprt can lead to LND with the development of the persistent and severe self-injurious behavior. Recently, a role for epistasis between the mutated hypoxanthine phosphoribosyltransferase 1 (<italic>HPRT1</italic>) and the β-amyloid precursor protein (APP) genes affecting the regulation of alternative APP pre-mRNA splicing in LND has been demonstrated. Furthermore, there were also some reported cases of LND developing thrombosis while APP is an important regulator of vein thrombosis and controls coagulation. Otherwise, the surface expression of HGprt enzyme was also observed in several somatic tissue cancers while APP and the APP-like protein-2 (APLP2) are deregulated in cancer cells and linked to increased tumor cell proliferation, migration, and invasion. The present review provides a discussion about these findings and suggests a potential molecular link between APP and HGprt via epistasis between <italic>HPRT1</italic> and <italic>APP</italic> genes affecting the regulation of alternative APP pre-mRNA splicing. As a perspective, expression vectors for HGprt enzyme and APP are constructed as described in Ref. # 24 (Nguyen KV, Naviaux RK, Nyhan WL (2020) Lesch-Nyhan disease: I. Construction of expression vectors for hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and amyloid precursor protein (APP). <italic>Nucleosides Nucleotides Nucleic Acids</italic> 39: 905–922), and they could be used as tools for clarification of these issues. In addition, these expression vectors, especially the one with the glycosyl-phosphatidylinositol (GPI) anchor can be used as a model for the construction of expression vectors for any protein targeting to the cell plasma membrane for studying intermolecular interactions and could be therefore useful in the vaccines as well as antiviral drugs development (studying intermolecular interactions between the spike glycoprotein of the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, as well as its variants and the angiotensin-converting enzyme 2, ACE2, in coronavirus disease 2019 (COVID-19) <xref ref-type="bibr" rid="b43">[43]</xref>,<xref ref-type="bibr" rid="b44">[44]</xref>, for example).</p> </abstract>

Optical Genome Mapping Reveals and Characterizes Recurrent Aberrations and New Fusion Genes in Adult ALL

“…Another member of this family, amyloid precursor protein, encoded by APP , was previously reported to be a clinically significant and prognostic factor in AML1-ETO cases [ 44 ]. Moreover, APP and APP-like protein-2 ( APLP2 ) are deregulated in cancer cells and linked to increased tumor cell proliferation, migration, and invasion [ 45 ]. NPM1 represents the most frequently mutated gene in AML, is known as a good prognostic marker, and thus might be of potential clinical significance and targeted therapy [ 46 ] in this patient.…”

Inborn Errors of Purine Salvage and Catabolism

“…Other relevant transcriptional alterations were involved in energy metabolism [ 74 ], cell differentiation and maturation [ 77 ], cAMP/PKA signaling [ 78 ], cell cycle and division, nucleic acid metabolism [ 75 ], and purinergic signaling [ 79 ]. Nguyen [ 80 ] has suggested that epistasis between mutated HPRT1 and amyloid precursor protein ( APP ) genes may affect the APP splicing, producing alternative APP fragments that might be responsible for the neurobehavioral syndrome.…”

Hypoxanthine guanine phosphoribosyltransferase 1, a target of miR-125b-5p, promotes cell proliferation and invasion in head and neck squamous cell carcinoma

“…Hypoxanthine guanine phosphoribosyltransferase 1 (HPRT1) is a rate-limiting enzyme in the DNA salvage pathway, whose activity is critical to maintaining the purine pool and promoting cell cycle progression through the regulation of guanine and inosine production [ 3 , 4 ]. Although it is broadly regarded as a housekeeping gene, recent studies have demonstrated the differential expression level of HPRT1 between malignant and normal tissues, implying that it may play functional roles in tumorigenesis and is unreliable as an endogenous control in cancer-related studies [ [5] , [6] , [7] , [8] ].…”