Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients

Abstract

Mature-onset diabetes of the young, type 2 (MODY2) is associated with mutations in the glucokinase (GCK) gene that result in impaired glucokinase activity. Although more than 200 inactivating GCK mutations have been reported, only less than 20% of these mutations have been functionally characterized. In this work, we describe the biochemical characterization of six missense glucokinase mutations associated with MODY2 from Spanish patients, namely, Y61S, V182L, C233R, E265K, A379V, and K420E. All these mutations produced enzymes that presented reduced enzymatic activity in various degrees, from a mild affectation (K420E) to a more severe effect (C233R). Mutation severity correlated with the importance of the structural changes introduced by the mutations. For example, C233R affected a critical residue of the active center of the enzyme and rendered a protein with undetectable enzymatic activity. These data add new information on the structure-function relationship of human glucokinase.

Identification and analysis of novel R308K mutation in glucokinase of type 2 diabetic patient and its kinetic correlation

“…In the present study, the genetic analysis of 10th exon of patient's GK gene showed G to A mutation corresponding to R308K. Several mutations have been reported so far in GK, which are primarily attributed in hyperglycemic condition observed in several ethnic populations across the globe [10,[44][45][46].…”

The glucokinase mutation p.T206P is common among MODY patients of Jewish Ashkenazi descent

“…Our bioinformatics model suggested an effect of the p.T206P mutation on amino acids p.M210 and p.C233, previously found to be essential for GCK enzymatic activity (18,19). Interestingly, a homozygous p.M210K substitution has been reported in neonatal diabetes (18).…”

“…The concentration of ATP required for GCK activity to be half-maximal when glucose is in excess was increased by a factor of 3.9 (18). Biochemical characterization of the p.C233R substitution (19) showed that p.C233R affected a critical residue of the active center of the enzyme and rendered a protein with undetectable enzymatic activity. In the present study, bioinformatics modeling located p.T206 at the substrate-binding cleft.…”

Stress Hyperglycemia: A Sign of Familial Diabetes in Children

“…Indeed, genetic analysis revealed 2 different heterozygote mutations in the GCK gene known to cause maturityonset diabetes of the young (MODY) 2. The c697T3 C p.C233R mutation found in patient 1 has been detected in Spanish patients, 11 whereas the c616A3 C p.T206P mutation identified in patient 2 was first reported by our laboratory and was found in 3 unrelated families of Ashkenazi Jewish origin. 12 Heterozygous mutations in the GCK gene lead to decreased activity of the GCK enzyme that catalyzes the first and ratelimiting step of glucose metabolism in ␤ cells, which results in a mild form of DM.…”