Genetic basis of inosine triphosphate pyrophosphohydrolase (ITPA) deficiency

Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a common inherited condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes. The genetic basis and pathological consequences of ITPase deficiency are unknown. We have characterized the genomic structure of the ITPA gene, showing that it has eight exons. Five single nucleotide polymorphisms were identified, three silent (138GMA, 561GMA, 708GMA) and two associated with ITPase deficiency (94CMA, IVS2+21AMC). Homozygotes for the 94CMA missense mutation (Pro32 to Thr) had zero erythrocyte ITPase activity, whereas 94CMA heterozygotes averaged 22.5% of the control mean, a level of activity consistent with impaired subunit association of a dimeric enzyme. ITPase activity of IVS2+21AMC homozygotes averaged 60% of the control mean. In order to explore further the relationship between mutations and enzyme activity, we examined the association between genotype and ITPase activity in 100 healthy controls. Ten subjects were heterozygous for 94CMA (allele frequency: 0.06), 24 were heterozygotes for IVS2+21AMC (allele frequency: 0.13) and two were compound heterozygous for these mutations. The activities of IVS2+21AMC heterozygotes and 94CMA/IVS2+21AMC compound heterozygotes were 60% and 10%, respectively, of the normal control mean, suggesting that the intron mutation affects enzyme activity. In all cases when ITPase activity was below the normal range, one or both mutations were found. The ITPA genotype did not correspond to any identifiable red cell phenotype. A possible relationship between ITPase deficiency and increased drug toxicity of purine analogue drugs is proposed.

The Genetic Speciation of Archaeological Fish Bone: A Feasibility Study from Southeast Queensland

Current genetic methods enable highly specific identification of DNA from modern fish bone. The applicability of these methods to the identification of archaeological fish bone was investigated through a study of a sample from late Holocene southeast Queensland sites. The resultant overall success rate of 2% indicates that DNA analysis is, as yet, not feasible for identifying fish bone from any given site. Taphonomic issues influencing the potential of genetic identification methods are raised and discussed in light of this result.