Genetic basis of hemolytic anemia caused by pyrimidine 5 ' nucleotidase deficiency

Pyrimidine 5' nucleotidase (P5'N-1) deficiency is an autosomal recessive co ndition causing hemolytic anemia characterized by marked basophilic stippli ng and the accumulation of high concentrations of pyrimidine nucleotides wi thin the erythrocyte, It is implicated in the anemia of lead poisoning and is possibly associated with learning difficulties. Recently, a protein with P5'N-1 activity was analyzed and a provisional complementary DNA (cDNA) se quence published. This sequence was used to study 3 families with P5'N-1 de ficiency. This approach generated a genomic DNA sequence that was used to s earch GenBank and identify the gene for P5'N-1, It is found on chromosome 7 , consists of 10 exons with alternative splicing of exon 2, and produces pr oteins 286 and 297 amino acids long. Three homozygous mutations were identi fied in this gene in 4 subjects with P5'N-1 deficiency: codon 98 GAT --> GT T, Asp --> Val (linked to a silent polymorphism codon 92, TAC --> TAT), cod on 177, CAA --> TAA, Gln --> termination, and IVS9-1, G -->T. The latter mu tation results in the loss of exon 9 (201 bp) from the cDNA. None of these mutations was found in 100 normal controls. The DNA analysis was complicate d by P5'N-1 pseudogenes found on chromosomes 4 and 7, This study is the fir st description of the structure and location of the P5'N-1 gene, and 3 muta tions have been identified in affected patients from separate kindreds, (Bl ood, 2001;97:3327-3332) (C) 2001 by The American Society of Hematology.