Disease relevance of GK2

• The gene loci for adrenal hypoplasia congenita (AHC) and glycerol kinase deficiency (GK) map in Xp21 distal to Duchenne muscular dystrophy (DMD), and proximal to DXS28 (C7), by analysis of patient deletions [1].
• Mapping of the individuals' missense mutations to the three-dimensional structure of Escherichia coli GK revealed that the symptomatic individuals' mutations are in the same region as a subset of the mutations among the asymptomatic individuals, adjacent to the active-site cleft [2].
• Glycerokinase activity in human adipose tissue as related to obesity [3].
• In these individuals, weight loss is more difficult since they tend to reutilize the glycerol formed by lipolysis and net glycerokinase activity in their adipose tissue may reflect variations in lipid turnover [3].
• We have investigated GK activity and subcellular distribution of muscle GK in DMD patients and in a patient with the complex GKD syndrome presenting with myopathy [4].

Psychiatry related information on GK2

• Patient 4 had both GK deficiency with mental retardation and a GK missense mutation (D440V) [5].

High impact information on GK2

• We identified expressed sequences within a cosmid in the glycerol kinase (GK) "critical region" of Xp21 that had impressive similarity to prokaryotic GKs [6].
• Homogenates of the patient's leukocytes contained negligible activity of ATP:glycerol phosphotransferase (glycerokinase EC 2.7.1.30) as measured by a direct spectrophotometric method [7].
• Resequencing of the GK gene in family members led to the discovery of a N288D missense mutation in exon 10, which resulted in the substitution of a highly conserved asparagine residue by a negatively charged aspartic acid [8].
• Glycerol kinase (GK) represents the primary entry of glycerol into glucose and triglyceride metabolism [8].
• Linkage analysis of the data from 12 microsatellite markers surrounding the Xp21.3 GK gene resulted in a peak LOD score of 3.46, centered around marker DXS8039 [8].

Chemical compound and disease context of GK2

• Mutations of GK in man can be inactivating, to cause a form of diabetes mellitus, or activating, to lower blood glucose levels [9].
• Acetylcholine (ACh) binding to atrial muscarinic receptors activates an inwardly rectifying K+ current (IK[ACh]) via a pertussis toxin-sensitive GTP-binding protein (GK) [10].

Biological context of GK2

• We have constructed a yeast artificial chromosome (YAC) contig encompassing a 1.2 Mb region extending distally from DMD, and containing DXS708 (JC-1), the distal junction clone of a patient with GK and DMD [1].
• Thus SLC37A1 mutations may cause a phenotype similar to GK deficiency [11].
• We conclude that, like many other disorders, GK genotype does not predict GKD phenotype [2].
• To better understand the pathogenesis of isolated GKD, we sought individuals with point mutations in the GK coding region and measured their GK enzyme activities [2].
• Lipase helps the breakdown of triacylglycerol to yield free fatty acids and glycerol, while glycerokinase catalyzes the adenosine-5-triphosphate-dependent phosphorylation of glycerol to yield alpha-glycerol phosphate, which can subsequently be oxidized by 3-glycerol phosphate oxidase to produce hydrogen peroxide [12].

Anatomical context of GK2

• In rats and mice, BAT has been demonstrated to possess a much higher glycerokinase activity than white adipose tissue (WAT) [13].
• GK activity measured in lymphoblastoid cell lines or fibroblasts was similar for the symptomatic and the asymptomatic individuals [2].
• The presence of glycerokinase has been demonstrated in human omental and subcutaneous adipose tissue [14].
• Enzyme activity of glycerol-kinase (ATP:glycerol-3-phosphotransferase, EC 2.7.1.30) in the cultured amniotic fluid cells was very low [15].
• In contrast, glycerokinase activity in rat adipocytes was decreased by fasting 48 hr and returned toward normal levels after refeeding for 36 hr [16].

Associations of GK2 with chemical compounds

• In patient 2 with a considerable activity of the GK enzyme (22% of reference), oxidation to [(14)C]CO(2) (37%) and a high incorporation of [(14)C] into macromolecules (92%), we identified a c.182T>C (L61P) mutation that causes the enzyme to have a higher K(m) for glycerol ( approximately 300 microM) than normals (2-8 microM) [17].
• Glycerol-3-phosphate dehydrogenase was not detected in this tissue but an active glycerokinase was demonstrated in the cytosolic fraction [18].
• The best and most effective configuration found for the measurement of glycerol and triacylglycerols in this system was the tandem connection of a lipase column and a silica-fused capillary column coimmobilized with glycerokinase (GK) and glycerol-3-phosphate oxidase (GPO) [12].
• 1-thioglycerol (1-TG) was investigated as a potential GK inhibitor in adrenal gland, an organ consistently affected, and in cultured fibroblasts, available from affected individuals [19].
• Glycerokinase activity was also significantly increased following prolonged incubation of rat adipocytes with dexamethasone in vitro [16].

Analytical, diagnostic and therapeutic context of GK2

• Sequence analysis revealed that the larger bands represented the wild-type GK RNA and smaller bands represented mutant misspliced RNA, suggesting that the abnormal RNA species were targeted by NMD [20].
• The proposed biosensing system using lipase, GK, and GPO exhibited a flow-injection analysis peak response of 2.5 min and a detection limit of 5 x 10(-5) M glycerol (S/N = 3) with acceptable reproducibility (CV < 4.30%) [12].
• Mutation screening of the GK gene was performed by amplification and direct sequencing of exons using PCR [21].
• One of the boys with DMD, GK, and AHC is shown by pulsed-field-gel electrophoresis to have a deletion which has a proximal endpoint at least 500 kb distal from the pERT87 (DXS164) locus [22].
• Immunocytochemistry demonstrated that G-kinase translocated from a diffuse localization in the cytoplasm to the cytoskeleton after stimulation with A23187 [23].

References