Five cases of isolated glycerol kinase deficiency, including two families: failure to find genotype:phenotype correlation

Abstract

Little is understood of the genotype/ phenotype correlations in X linked glycerol kinase deficiency (GKD) where most cases are caused by extensive deletions of Xp21, which often include genes flanking the GK locus. Few cases of isolated GKD have been investigated where the phenotype is not influenced by neighbouring genes. In this paper, we present the mutation data from four confirmed and one suspected case of non-deletion, isolated, X linked GKD and therefore extend the base of patients that can allow an assessment of genotype/phenotype correlations for this disease. The mutations found were two terminations leading to premature truncation of the GK polypeptide chain, one insertion, and an amino acid substitution. Phenotypic variation was observed in two families, where there was more than one aVected subject carrying the same mutation, confirming previous studies that suggest there is no correlation between disease severity and genotype. Furthermore, the nature of the mutation in diVerent families does not appear to influence the spectrum of phenotypic variation. In addition, one coding polymorphism in exon 3 has been found. The characterisation of the gene structure has been completed and shows that instead of 19 there are 21 exons. (J Med Genet 2000;37:434-441)

Glycerol kinase deficiency: residual activity explained by reduced transcription and enzyme conformation

“…RNA analysis proved that he had a mutation in the GK gene and thus the isolated form of GKD and not the complex form, as it is defined to be caused by deletion of different loci in the p21 region of the X chromosome. As the g.16835G4A mutation has recently been described in another patient with isolated GKD, normal creatine kinase activity and adrenal function, 10 it is unlikely that this mutation could explain the complex clinical picture in our patient. The possibility of another gene defect occurring together with the insertion in the GK gene cannot be excluded.…”

“…Several cases with a GK activity 45% have been reported earlier. Sargent et al 10 have described a C256R substitution in a patient with 12% GK activity. This amino-acid residue is located in a b-sheet close to domains involved in ATP binding, 22 and this may result in an enzyme with some residual activity.…”

“…AJ252550-AJ252560, AJ252563-AJ252570), 19 were amplified using genomic primers as described previously. 1,10,17 To analyze exons 10 and 11, the Expandt High Fidelity PCR system (Boehringer Mannheim, Germany) was used to amplify the long DNA fragments comprising exons 8 -11 according to the manufacturer's instruction as described previously. 1 Sequencing was performed using the dRhodamine dye terminator cycle sequencing kit (Perkin-Elmer) and the products were analyzed on an ABI 377 sequencer (Applied Biosystemst, Foster City, CA, USA).…”

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

“…Previous studies have shown no correlation between genotype (mutations in the GK gene) and phenotype (symptomaticity) in affected individuals. For example, the same GKD mutation was observed in both a symptomatic and an asymptomatic individual [12], and this discrepancy was also reported in two brothers with the identical mutation [13]. The glycerol phosphorylating activity of GK in lymphoblastoid cell lines or fibroblasts from symptomatic and asymptomatic individuals was similar.…”

“…5 lists the steady-state mass isotopomer abundances of the non-essential amino acids Pro, glutamate and glutamine (Glx), aspartate and asparagine (Asx), glycine (Gly), serine (Ser), and alanine (Ala), at the end of passage 2. The mass isotopomers of amino acid fragments including Gly [12], Ser [12], Ser [23], Ser[123], Asx [12], Asx[234], and Asx[1234], displayed significant differences (4.0 to 6.0 times the biological standard error) between the GKoverexpressing cell lines and the wild type (p < 0.03, Fig. 5).…”