Six Previously Undescribed Pyruvate Kinase Mutations Causing
Enzyme Deficiency
Anna Demina,
Kottayil I. Varughese,
José Barbot,
Linda Forman, and
Ernest Beutler
From the Department of Molecular and Experimental Medicine, The
Scripps Research Institute, La Jolla, CA; and the Serviço de
Hematologia, Hospital Central Especializado, de Crianças Maria
Pia, Rua da Boavista, Porto, Portugal.
Erythrocyte pyruvate kinase deficiency is the most common cause of
hereditary nonspherocytic hemolytic anemia. We present 6 previously
undescribed mutations of the PKLR gene associated with enzyme
deficiency located at cDNA nt 476 G
T
(159GlyVal), 884 CT
(295AlaVal), 943 GA
(315GluLys), 1022 GA
(341GlyAsp), 1511 GT
(504ArgLeu), and 1528 CT
(510ArgTer). Two of these mutations are near the
substrate binding site: the 315GluLys (943A)
mutation may be involved in Mg2+ binding and
159GlyVal (476T) mutation has a possible effect
on ADP binding. Four of six mutations produce deduced changes in the
shape of the molecule. Two of these mutations,
504ArgLeu (1511T) and
510ArgTer (1528T), are located at the interface
of domains A and C. One of them (510ArgTer) is a
deletion of the C-terminal residues affecting the integrity of the
protein. The 504ArgLeu mutation eliminates a
stabilizing interaction between domains A and C. Changes in amino acid
341(nt 1022) from Gly to Asp cause local perturbations. The mutation
295AlaVal (884T) might affect the way pyruvate
kinase interacts with other molecules. We review previously described
mutations and conclude that there is not yet sufficient data to allow
us to draw conclusions regarding genotype/phenotype relationship.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 647-652
© 1998 by the American Society of Hematology.
