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1. Foundation of the hypothesis
Core hypothesis: translocation rates, poly Asparagine (Asn); insulin-receptor-substrate 2 (IRS2) and diabetes; hypothesis tests, poly glutamine (Gln) HTT and ataxias
Despite similar Asn codon usage, ~4%/gene, from plants to humans (1), mammals are distinguished by a paucity of genes with a long Asn homopolymeric coding region (N-hCR) (2). The 17 human genes with the longest N-hCR (ranging from five to eight consecutive Asn codons) are listed in Fig. 1; Table I lists genes with N-hCR greater than three. IRS2, encoding an insulin signal transducer, is the gene at the top of the list in Fig. 1 and multiple disorders of energy homeostasis and the urea cycle are associated with genes in Table I. The central hypothesis of this paper is that manifestations of these disorders may partly be attributable to reduced plasma Asn concentrations, which in turn may disproportionately affect the production of proteins containing N-hCR. More broadly, we propose a model in which protein expression may be affected at amino acid homopolymeric coding regions (hCR) in general because translation elongation rates at hCR could reflect variation in the levels of the corresponding amino acids. This model may contribute to explaining an association, initially noted with poly Gln codon runs, between hCR and some human diseases (1,3).
Asparaginase (ASNase) is a component of highly effective chemotherapeutic regimens used to treat pediatric acute lymphoblastic leukemia (ALL) (4,5) and some lymphomas (6–8). ASNase treatment has been estimated to have contributed to the sparing of the lives of upwards of 60,000 children in the US in the decades following its discovery (9) and rapid introduction to the clinic (10). However, ASNase treatment is not without hazard; it can produce a myriad of side-effects that include hyperglycemia, dislipidemia, pancreatitis, vascular accidents and adverse neurological outcomes. The physiological mode of action of ASNase is unclear. The enzyme deaminates Asn and Gln with production of altered amino acid ratios and ammonia (11–15). ASNase inhibits synthesis of proteins in vitro (16) and in vivo (17,18) by a mechanism consistent with reduced ribosomal translocation at Asn codons. In humans, ASNase treatment protocols cause depletion of plasma Asn and modest reductions of plasma Gln levels accompanied by mild transient hyperglycemia and occasional ketoacidosis (11,19,20). In mice, administration...