Pyruvate kinase deficiency in France: a 3‐year study reveals 27 new mutations

Abstract

Summary Pyruvate kinase (PK) deficiency is the most common enzyme defect affecting the glycolytic pathway of the erythrocyte. Usually, it is clinically silent in heterozygotes but serious disorders are described at birth in homozygotes or compound heterozygotes. Including the mutants herein reported, more than 180 mutations of the PK‐LR gene have now been identified. This 3‐year study was carried out to detect mutations associated with disease‐affecting families. Haematological indices, erythrocyte PK and glucose‐6‐phosphate dehydrogenase activities were measured. Molecular characterisation of the PK gene mutations included restriction enzyme analysis, mutation scanning and gene sequencing. Among the 56 families studied, nine homozygous cases and 41 different mutations were found. Eight mutations involved a splice site, 31 missense mutations were located in crucial domains of the molecule (catalytic site, cleft between the A and C domains, A/A’ interface) and two cases of insertion–deletion were found. In total, 20 new mutations modifying the structure of the enzyme and seven affecting a splice site are reported. PK deficiency is an under diagnosed disease. However, deficiency could be life threatening in perinatal period and we report two lethal cases. These results support the characterisation of PK mutations, and show that prenatal diagnosis can identify affected infants and prepare safer conditions for the birth.

Fifteen novel mutations inPKLRassociated with pyruvate kinase (PK) deficiency: Structural implications of amino acid substitutions in PK

“…Amino acid substitutions in the B domain are rare and only seven mutations have been described thus far Kugler et al, 2000;Neubauer et al, 1991;Pissard et al, 2006;Zanella et al, 1997]. The side chain of Arg163 points into the cleft between the A and B domains where the active site is located.…”

“…Pissard et al [2006Pissard et al [ , 2007 recently reported the c.375110G4T change to be associated with PK deficiency, either on itself or in cis with missense mutations c.1178A4G (p.Asn393Ser) and c.359C4T (p.Ser120Phe). They did not detect the c.375110G4T change in their normal controls (n 5 100).…”

Erythrocyte Pyruvate Kinase Deficiency mutation identified in multiple breeds of domestic cats

“…Subsequent population studies have increased this total by over 44 novel mutations [18,44]. Mutations are found in every exon, as well as several introns, all of which result in human PK deficiency.…”

Point Mutations That Reduce Erythrocyte Resistance to Oxidative Stress

“…Two mutations, both located in exon 11, are recurrent (Arg510 → Gln, Arg486 → Trp). Arg510→ Gln is the most frequent mutation found in northern Europe, central Europe and the USA (Pissard S. at al., 2006, as citated Wang et al, 2001) and Arg486 → Trp in southern Europe (Spain, Portugal and Italy) and in France (Pissard et al, 2006, as citited Zanella et al, 1997Zarza et al, 1998;Pissard et al, 2006). The most frequent mutations of PKLR gene in the Indian population appear to be 1436G→A (19.44%), followed by 1456C→T (16.66%) and 992A→G (16.66%) (Kedar et al, 2009).…”