About the PKLR Mutation Database

This mutation database lists all mutations in the human PKLR gene. This gene encodes the liver- and red blood cell-specific isoform of the glycolytic enzyme pyruvate kinase (PK). Currently, this database contains a total number of 193 mutations. In all but one cases, these mutations have been associated with deficient enzyme function. The one exception concerns a mutation that has been associated with elevated red blood cell PK activity.
In the PKLR Mutation Database, mutations are categorized according to the molecular mechanism by which they exert their effect on gene expression and/or protein function. These categories are:

I. Nonfunctional mRNA
   a. nonsense mutants
   b. frameshift mutants
II. RNA processing
   a. splice junction changes
   b. consensus changes - intronic
   c. consensus changes - exonic
   d. intronic substitutions - affecting processing
   e. exonic substitutions - affecting processing
III. Transcriptional mutants
IV. Coding region substitutions*
   a. missense mutants
   b. in-frame deletions
   c. in-frame insertions
V. Deletional mutants
VI. Mutations associated with elevated red cell PK activity

* The majority of mutations concern missense mutations. With regard to this specific group of mutations, the protein structural context of the affected residues was evaluated and the molecular perturbation upon mutation was predicted using the three-dimensional model of human PK (PDB entry: 1LIU). The results of these analyses are abbreviated and displayed in the database. For illustrative purposes, overviews and (animated) close-up views at the site of mutation have been generated for each missense mutant.

List of abbreviations:

AS: Active Site; the affected residue is located in the active site, including PEP binding site and metal ion binding sites

BH: Buried Hydrophobic; the affected residue is buried in the hydrophobic core

DI: Domain Interface; residing at the N, A, B, or C domain, the affected residue is located at the domain interface, interacting with residues at the A [DI(A)], B [DI(B)], C [DI(C)] or N [DI(N)] domain

DL: Domain Linker; the affected residue is located at the boundary between two domains of the same subunit

DS: the amino aid substitution predicts the Disruption of Secondary structure (e.g. introduction of a proline residue in the middle of a strand or helix)

HB: Hydrogen Bond; the encoded amino aid substitution predicts the disturbance of the local network of hydrogen bonds

HI: the amino acid substitution predicts the loss of Hydrophobic Interaction

LC: the amino acid substitution predicts the Loss of Charged contact

LH: Leaves a Hole; a buried side chain is replaced by a smaller side chain – the resulting hole must be filled up with water or a structural rearrangement must occur

NA: the affected residue is located Near or at the ATP binding site

NE: conservative mutation in a surface exposed residue; evaluation of the structure suggests No obvious Effect of mutation

NF: the affected residue is located Near or at the FBP binding site

RA: substitution or introduction of glycine and proline residues causes main chain dihedral π and ψ to lie in an energetically unfavorable region of the RAmachandran plot

SH: Sterical Hindrance; the mutant side chain needs more room than is available

SI: Subunit Interface; the affected residue is located in the interface of two subunits. Either the A/A’[SI(A)], C/C’ [SI(C)], A/N’ [SI(AN)], or N/A' [SI(NA)] can be involved. The mutation may disturb allosteric interactions

TU: the affected amino acid is located in a tight TUrn

UC: the amino acid substitution predicts introduction of an Unfavourable Charge interaction and/or removal of a favourable charge interaction