PK-LR gene mutations in pyruvate kinase deficient Portuguese patients.

Summary. In nine unrelated Portuguese patients withpyruvate kinase (PK) deficient anaemia, whose symptomsranged from a mild chronic haemolytic anaemia to a severeanaemia presenting at birth and requiring multiple trans-fusions, the PK-LR gene mutations were identified andcorrelated with their phenotypes. Five different mutationswere identified, three of them for the first time: a missensemutation 1670G !C on exon 12 and two 5 0 splice donor site(GT) mutations on intron 8 [IVS8(þ2)T !G] and intron 10[IVS10(þ1)G !C]. Two previously described missensemutations, 1456C !T and 993C !A, were also found.The genotype/phenotype correlation showed that patientswith two missense mutations or with a missense mutationand a splicing mutation had a mild haemolytic anaemia. Thethree patients with severe anaemia, who were transfusiondependent until splenectomy, were homozygous for thesplicing site mutations IVS10(þ1)G !C or IVS8(þ2)T !G. Keywords: pyruvate kinase deficiency, human PK-LR genemutations, haemolytic anaemia, splice site, Portugal.Pyruvate kinase (PK EC 2.7.1.40) deficiency is the mostcommon enzyme abnormality in the erythrocyte glycolyticpathway causing hereditary nonspherocytic haemolyticanaemia (HNSHA). The PK-deficient anaemia is transmittedas an autosomal recessive disorder with a heterogenousclinical phenotype, ranging from a mild chronic haemolyticanaemia to a severe anaemia presenting at birth andrequiring exchange transfusion. Splenectomy is effective indecreasing haemolysis in most patients. Heterozygotes areusually asymptomatic, with a 30–50% decrease in the PKactivity levels (Miwa