Adenine phosphoribosyltransferase (APRT) deficiency: identification of a novel nonsense mutation

Abstract

BackgroundAdenine phosphoribosyltransferase deficiency (APRTD) is an under estimated genetic form of kidney stones and/or kidney failure, characterized by intratubular precipitation of 2,8-dihydroxyadenine crystals (2,8-DHA). Currently, five pathologic allelic variants have been identified as responsible of the complete inactivation of APRT protein.Case presentationIn this study, we report a novel nonsense mutation of the APRT gene from a 47- year old Italian patient. The mutation, localized in the exon 5, leads to the replacement of a cytosine with a thymine (g.2098C > T), introducing a stop codon at amino acid position 147 (p.Gln147X).This early termination was deleterious for the enzyme structural and functional integrity, as demonstrated by the structure analysis and the activity assay of the mutant APRT protein.ConclusionThese data revealed that the p.Gln147X mutation in APRT gene might be a new cause of APRT disease.

Fibril formation and therapeutic targeting of amyloid-like structures in a yeast model of adenine accumulation

“…Purine biosynthesis pathways are crucial for the normal function of cells and are conserved between yeast and humans. Both the adenine phosphoribosyltransferase (APRT) and adenosine deaminase (ADA) enzymes take part in adenine salvage in humans and mutations in their encoding genes can lead to the accumulation of adenine and its derivatives 22,23 . Mutation in APRT leads to the APRT deficiency and mutation in ADA leads to ADA deficiency.…”

“…The recent extension of the amyloid hypothesis offers opportunities for both diagnostics, as well as therapy of these disorders. Specifically, inborn mutations in genes involved in the adenine salvage pathway in humans can lead to the development of several metabolic disorders as a result of the accumulation of adenine and its derivatives 22,23 . We have previously shown the formation of adenine amyloid-like structures in vitro.…”

Asparaginase treatment side-effects may be due to genes with homopolymeric Asn codons (Review-Hypothesis)

“…Altered Asn levels could shift the balance between CKS2 and CKS1B to affect cell cycle regulation in multiple cancers including ALL, and, via PPP1R13B, senescence in normal cells ( 387 ). Other notable genes devoid of Asn codons are mus APRT (kidney stones) ( 388 ) and human BIRC7 (ALL prognosis) ( 389 ), LOR ( cf . Staph.…”

Febuxostat for the Prevention of Recurrent 2,8-dihydroxyadenine Nephropathy due to Adenine Phosphoribosyltransferase Deficiency Following Kidney Transplantation

“…The APRT gene, which is located on chromosome 16q24, is approximately 2.6 kb long, contains 5 exons and 4 introns, and encodes the 180-amino acid protein APRT ( 5 ). The mutant alleles responsible for type I and II APRT deficiency are classified as APRT*Q0 (complete enzyme deficiency in vivo and in vitro ) ( 1 ) and APRT*J (complete enzyme deficiency in vivo but partial deficiency in vitro ), respectively.…”

“…APRT deficiency is a rare (at least 1:50,000 to 1:100,000) autosomal recessive disorder that results in irreversible renal damage and subsequent chronic kidney disease (CKD) due to the deposition of 2,8-DHA in the renal tubules ( 5 ). Unfortunately, APRT deficiency is under-recognized by physicians, and its diagnosis is often delayed for many years.…”