title: Molecular and clinical heterogeneity in pyruvate kinase deficiency in India.
abstract: We studied the PK-LR gene in 10 unrelated Indian patients with congenital haemolytic anemia associated with erythrocyte pyruvate kinase deficiency. The patients had a variable presentation ranging from a very mild compensated hemolysis to severe anemia. Nine different mutations were detected among the 20 mutated alleles identified: one deletion (c.1042-1044del) p.Lys348del and eight single-nucleotide (nt) substitutions resulting in amino acid exchanges c.397A>G (p.Asn133Asp), c.992A>G (p.Asp331Gly), c.1072G>A (p.Gly358Arg), c.1076G>A (p.Arg359His), c.1219G>A (p.Glu407Lys), c.1241C>T (p.Pro414Leu), c.1436G>A (p.Arg479His) and c.1529G>A (p.Arg510Gln) were identified. Although all the exons, the flanking regions and the promoter region were sequenced in all cases, we failed to detect the second expected mutation in two subjects. Two mutations [c.397A>G; c.1241C>T] were novel. These novel missense mutations involved highly conserved amino acids. Two mutations were identified for the first time in the homozygous state globally (c1042-1044del; c.1072G>A) and two other mutations were identified for the first time in our population (c.1076G>A; c.1529G>A). This study along with our earlier report suggests that the most frequent mutations in India would appear to be c.1436G>A (18.33%), followed by c.992A>G (11.66%) and c.1456C>T (11.66%). Structural implications of amino acid substitutions were correlated with the clinical phenotypes seen.
authors.affiliation: National Institute of Immunohaematology (Indian Council of Medical Research), K.E.M. Hospital Campus, Parel, Mumbai, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Warang
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Kedar
authors.forename: Kanjaksha
authors.initials: K
authors.lastname: Ghosh
authors.forename: Roshan
authors.initials: R
authors.lastname: Colah
mesh_terms: D000293:Adolescent; D000483:Alleles; D000746:Anemia, Hemolytic, Congenital Nonspherocytic / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007194:India; D007223:Infant; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011770:Pyruvate Kinase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D015323:Pyruvate Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult
chemical_list: D011770:Pyruvate Kinase
keywords: Glycolytic enzymes; Hemolytic anemia; Molecular modeling; Pyruvate kinase; Red cell enzymes