PENELITIAN

GLYCEROL KINASE; GK

Alternative titles; symbolsATP:GLYCEROL PHOSPHOTRANSFERASEGene map locus Xp21.3-p21.2

TEXT

DESCRIPTION

Glycerol kinase (EC 2.7.1.30) catalyzes the phosphorylation of glycerol by ATP, yielding ADP and glycerol-3-phosphate.

CLONING

Sargent et al. (1993) isolated and sequenced cDNA clones from a human adult testis cDNA library to produce expressed sequence tags (ESTs). Using these ESTs to search DNA and protein sequence databases, Sargent et al. (1993) isolated a cDNA clone that showed 60% identity to the Bacillus subtilis glycerol kinase gene at both the DNA and amino acid sequence levels. Analysis of DNA from somatic cell hybrids carrying deleted X chromosomes showed that this clone detected homologous sequences between Xp22.1-p21.2, the interval containing the locus responsible for glycerol kinase deficiency (307030). In a commentary, Willard (1993) pointed out the usefulness of the EST strategy for cataloging new genes. Sargent et al. (1994) reported that Northern analysis showed expression of GK transcripts of 3 sizes in a wide range of adult tissues. Only the smallest hybridizing species was present in testis, where it occurred at an elevated level. 30 PubMed Neighbors

Simultaneously and independently, Walker et al. (1993) used positional cloning to isolate the human Xp21 GK gene. Using exon amplification products prepared from Xp21.3 cosmids mapping in the 50- to 250-kb GK critical region, according to the method of Buckler et al. (1991), Walker et al. (1993) screened a fetal liver cDNA library and identified 6 overlapping clones that encoded a partial predicted 395-amino acid protein with significant homology to the bacterial GK protein. Northern blot analysis showed 3 GK mRNA transcript sizes of 1.85, 2.7, and 3.7 kb. Expression of the GK gene was found in several human tissues, including skeletal muscle, kidney, and brain, with the highest expression in liver. 30 PubMed Neighbors

Guo et al. (1993) stated that the methods for screening total human DNA or YAC and cosmid clones for expressed sequences include interspecies cross-hybridization (‘zoo blots’), CpG island mapping, homologous recombination, hybridization of cDNAs to genomic clones, evaluation of nuclear RNA from somatic cell hybrids, exon trapping, hybridization of genomic (YAC) DNA to cDNA libraries, and random cDNA sequencing. These methods suffer from low efficiency and high background. Guo et al. (1993) described an efficient, sensitive and specific method for identifying genes which they referred to as cDNA amplification for identification of genomic expressed sequences (CAIGES). The approach combined PCR, for nonspecific amplification of cDNA library inserts, with hybridization of the amplified and labeled cDNAs to Southern blots of cloned genomic material blocked with placental DNA. When a genomic restriction fragment is identified by hybridization with the amplified cDNA library, the fragment is used to select the corresponding cDNA clone and can be subcloned and sequenced for identification of exons. Using the CAIGES approach, Guo et al. (1993) were able to clone the entire human hepatic GK cDNA coding sequence, beginning with a cosmid from the GK ‘critical region’ of Xp21. Corroboration of the identity of the gene was obtained by functional complementation of GK-deficient E. coli mutants. The cDNA encodes a 524-amino acid protein with 62% and 77% similarity to the E. coli and B. subtilis GK proteins. 30 PubMed Neighbors

Mahbubul Huq et al. (1996) presented the sequence of a full-length mouse Gyk cDNA that is alternatively spliced in brain. Transient transfection of cDNA into COS-7 cells caused a marked elevation in glycerol kinase activity, confirming the functional identity of the cDNA.

GENE STRUCTURE

By analysis of cosmid and YAC clones, Sargent et al. (1994) showed that the GK1 locus on Xp21.3 is more than 50 kb long and comprises at least 19 exons. In contrast, the remaining members of the glycerol kinase gene family, located on chromosomes 1, 4, and Xq, appear to be intronless.

Sjarif et al. (1998) found 2 differences from the previously reported sequence. They demonstrated that exon 9 actually consists of 2 exons separated by an intron of 392 basepairs, increasing the number of exons of the GK gene from 19 to 20. Sjarif et al. (1998) also demonstrated 3 nucleotide differences in exon 19 as compared to the sequence published by Sargent et al. (1994). 30 PubMed Neighbors

Sargent et al. (2000) identified an additional 18-bp exon between exons 8 and 9, thus bringing the total number of exons to 21.

MAPPING

Sargent et al. (1994) determined that the X-linked human glycerol kinase gene maps to Xp21.3.

Mahbubul Huq et al. (1996) mapped the mouse Gyk gene to the mouse X chromosome by both fluorescence in situ hybridization and an interspecies backcross demonstrating conservation of synteny with dmd (310200).

Pseudogenes

Sargent et al. (1994) determined that the human glycerol kinase gene family consists of at least 6 genomic loci, 4 of which encode expressed sequences. They identified 2 different testis transcripts, both of which are encoded by chromosome 4. The genes on Xq and chromosome 1 were thought to be pseudogenes; the gene on chromosome 4 is processed and expressed. The authors suggested that these sequences probably arose through reverse transcriptase mediated events. By fluorescence in situ hybridization, the 2 chromosome 4 loci were positioned at 4q13 and 4q32 (see 600148 and 600149); the pseudogenes were located at 1q41 and Xq23. 30 PubMed Neighbors

MOLECULAR GENETICS

Sargent et al. (1993) found that the cDNA sequence corresponding to the GK gene was deleted in 2 patients with glycerol kinase deficiency.

In 4 patients with isolated glycerol kinase deficiency, Walker et al. (1996) identified 3 different mutations in the GK gene (300474.0001300474.0003). The authors noted widely differing phenotypes and suggested ascertainment bias; metabolic or environmental stress as a precipitating factor in revealing GK-related changes, as had previously been described in juvenile GK deficiency; and interactions with functional polymorphisms in other genes that alter the effect of GK deficiency on normal development. 30 PubMed Neighbors

In 3 families with isolated glycerol kinase deficiency, Sjarif et al. (1998) identified 3 mutations in the GK gene (300474.0004300474.0006). There were no apparent genotype/phenotype correlations in these families.

Sargent et al. (2000) described mutations In 5 children with glycerol kinase deficiency, Sargent et al. (2000) identified 5 mutations in the GK gene: 2 nonsense mutations, 1 insertion, and an amino acid substitution. There was no correlation between the nature of the mutation and the spectrum of phenotypic variation. Phenotypic variation was observed in 2 families in which more than 1 affected subject carried the same mutation, confirming previous studies suggesting that there is no correlation between disease severity and genotype. 30 PubMed Neighbors

Isolated GKD can be either symptomatic with episodic metabolic and CNS decompensation or asymptomatic with hyperglycerolemia and glyceroluria only. Dipple et al. (2001) studied individuals with point mutations in the GK coding region. Six had missense mutations: 4 in males who were asymptomatic and 2 in individuals who were symptomatic. GK activity measured in lymphoblastoid cell lines or fibroblasts was similar for the symptomatic and the asymptomatic individuals. Mapping of the missense mutations to the 3-dimensional structure of E. coli GK showed that the symptomatic individuals’ mutations were in the same region as a subset of the mutations among the asymptomatic individuals, i.e., adjacent to the active-site cleft. Dipple et al. (2001) concluded that, like many other disorders, GK genotype does not predict GKD phenotype. They proposed that GKD is a complex trait influenced by additional, independently inherited genetic factors. 30 PubMed Neighbors

ANIMAL MODEL

Mahbubul Huq et al. (1997) generated glycerol kinase-deficient mice by targeted disruption. Mutant male mice appeared normal at birth, but exhibited postnatal growth retardation, altered fat metabolism with profound hyperglycerolemia and elevated free fatty acids, autonomous glucocorticoid synthesis, and death by 3 to 4 days of age. Heterozygous females were healthy and biochemically normal. 30 PubMed Neighbors

ALLELIC VARIANTS
(selected examples)

.0001 GLYCEROL KINASE DEFICIENCY, ISOLATED [GK, IVS6AS, G-C, -1]

In a 61-year-old male of Belgian origin, referred for ‘refractory hypertriglyceridemia,’ Walker et al. (1996) identified a G-to-C transversion in the last nucleotide of intron 6, resulting in a splice site mutation causing premature termination of the GK protein. His general health was good despite GK deficiency (307030). 30 PubMed Neighbors

.0002 GLYCEROL KINASE DEFICIENCY, ISOLATED [GK, EX17DEL ]

In 2 brothers with glycerol kinase deficiency (307030), Walker et al. (1996) identified a deletion of exon 17 in the GK gene. The older brother had a severe phenotype with psychomotor retardation and growth delay, bone dysplasias, and seizures. whereas his younger brother had relatively normal development at age 3 years. In the cDNA sequence, Walker et al. (1996) found that exon 16 was spliced directly to the penultimate exon 18 as a result of deletion of exon 17. 30 PubMed Neighbors

.0003 GLYCEROL KINASE DEFICIENCY, ISOLATED [GK, ASP440VAL ]

In a male patient with hyperglycerolemia, glyceroluria, and isolated glycerol kinase deficiency (307030), Walker et al. (1996) identified an A-to-T change in exon 15 of the GK gene, resulting in an asp44-to-val (D44V) substitution.

.0004 GLYCEROL KINASE DEFICIENCY, ISOLATED [GK, 20-KB DEL ]

In a child with glycerol kinase deficiency (307030) who presented with metabolic acidosis in the first week of life, Sjarif et al. (1998) reported a deletion in the GK gene of at least 20 kb extending from exon 9 to at least the 3-prime end of the gene. His maternal grandfather and 2 cousins, who carried the same genetic and biochemical defect, had either minimal or no symptoms. 30 PubMed Neighbors

.0005 GLYCEROL KINASE DEFICIENCY, ISOLATED [GK, ARG413TER ]

In a child with glycerol kinase deficiency (307030) who presented at 3 years of age with ketoacidosis, Sjarif et al. (1998) reported a C-to-T transition in the GK gene, resulting in a nonsense mutation at codon 413 (arg413-to-ter; R413X).

.0006 GLYCEROL KINASE DEFICIENCY, ISOLATED [GK, TRP503ARG ] Review this SNP

In a boy with glycerol kinase deficiency (307030) who presented at 10 months of age with generalized seizures and psychomotor delay, Sjarif et al. (1998) reported a 1651T-C transition in the GK gene, resulting in a trp503-to-arg (W503R) substitution.

.0007 GLYCEROL KINASE DEFICIENCY, ISOLATED [GK, ALU INS, IVS4]

Zhang et al. (2000) reported the case of a male with benign isolated glycerol kinase deficiency (307030) who was incidentally identified after observation of pseudohypertriglyceridemia at the age of 36 years. DNA sequencing of the GK gene showed insertion of an AluY sequence in intron 4 (IVS4-52ins316alu) of the glycerol kinase gene. Although Alu insertions had been implicated in other disorders, and a closely related AluY element had been found as an insert in the C1 inhibitor gene (606860) in patients with hereditary angioedema (106100), this was the first case of glycerol kinase deficiency caused by an Alu insertion. 30 PubMed Neighbors

.0008 HYPERGLYCEROLEMIA [GK, ASN288ASP ]

In 5 French-Canadian families in which 18 males had severe hyperglycerolemia (307030) in an X-linked pattern of inheritance, Gaudet et al. (2000) found an asn288-to-asp (N288D) missense mutation in exon 10 of the GK gene.

REFERENCES

1. Buckler, A. J.; Chang, D. D.; Graw, S. L.; Brook, J. D.; Haber, D. A.; Sharp, P. A.; Housman, D. E. :
Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc. Nat. Acad. Sci. 88: 4005-4009, 1991.
PubMed ID : 1850845
2. Dipple, K. M.; Zhang, Y.-H.; Huang, B.-L.; McCabe, L. L.; Dallongeville, J.; Inokuchi, T.; Kimura, M.; Marx, H. J.; Roederer, G. O.; Shih, V.; Yamaguchi, S.; Yoshida, I.; McCabe, E. R. B. :
Glycerol kinase deficiency: evidence for complexity in a single gene disorder. Hum. Genet. 109: 55-62, 2001.
PubMed ID : 11479736
3. Gaudet, D.; Arsenault, S.; Perusse, L.; Vohl, M.-C.; St.-Pierre, J.; Bergeron, J.; Despres, J.-P.; Dewar, K.; Daly, M. J.; Hudson, T.; Rioux, J. D. :
Glycerol as a correlate of impaired glucose tolerance: dissection of a complex system by use of a simple genetic trait. Am. J. Hum. Genet. 66: 1558-1568, 2000.
PubMed ID : 10736265
4. Guo, W.; Worley, K.; Adams, V.; Mason, J.; Sylvester-Jackson, D.; Zhang, Y.-H.; Towbin, J. A.; Fogt, D. D.; Madu, S.; Wheeler, D. A.; McCabe, E. R. B. :
Genomic scanning for expressed sequences in Xp21 identifies the glycerol kinase gene. Nature Genet. 4: 367-371, 1993.
PubMed ID : 8401584
5. Mahbubul Huq, A. H. M.; Lovell, R. S.; Ou, C.-N.; Beaudet, A. L.; Craigen, W. J. :
X-linked glycerol kinase deficiency in the mouse leads to growth retardation, altered fat metabolism, autonomous glucocorticoid secretion and neonatal death. Hum. Molec. Genet. 6: 1803-1809, 1997.
PubMed ID : 9302256
6. Mahbubul Huq, A. H. M.; Lovell, R. S.; Sampson, M. J.; Decker, W. K.; Dinulos, M. B.; Disteche, C. M.; Craigen, W. J. :
Isolation, mapping, and functional expression of the mouse X chromosome glycerol kinase gene. Genomics 36: 530-534, 1996.
PubMed ID : 8884278
7. Sargent, C. A.; Affara, N. A.; Bentley, E.; Pelmear, A.; Bailey, D. M. D.; Davey, P.; Dow, D.; Leversha, M.; Aplin, H.; Besley, G. T. N.; Ferguson-Smith, M. A. :
Cloning of the X-linked glycerol kinase deficiency gene and its identification by sequence comparison to the Bacillus subtilis homologue. Hum. Molec. Genet. 2: 97-106, 1993.
PubMed ID : 8499912
8. Sargent, C. A.; Kidd, A.; Moore, S.; Dean, J.; Besley, G. T. N.; Affara, N. A. :
Five cases of isolated glycerol kinase deficiency, including two families: failure to find genotype:phenotype correlation. J. Med. Genet. 37: 434-441, 2000.
PubMed ID : 10851254
9. Sargent, C. A.; Young, C.; Marsh, S.; Ferguson-Smith, M. A.; Affara, N. A. :
The glycerol kinase gene family: structure of the Xp gene, and related intronless retroposons. Hum. Molec. Genet. 3: 1317-1324, 1994.
PubMed ID : 7987308
10. Sjarif, D. R.; Sinke, R. J.; Duran, M.; Beemer, F. A.; Kleijer, W. J.; Ploos van Amstel, J. K.; Poll-The, B. T. :
Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency. J. Med. Genet. 35: 650-656, 1998.
PubMed ID : 9719371
11. Walker, A. P.; Muscatelli, F.; Monaco, A. P. :
Isolation of the human Xp21 glycerol kinase gene by positional cloning. Hum. Molec. Genet. 2: 107-114, 1993.
PubMed ID : 8499898
12. Walker, A. P.; Muscatelli, F.; Stafford, A. N.; Chelly, J.; Dahl, N.; Blomquist, H. K.; Delanghe, J.; Willems, P. J.; Steinmann, B.; Monaco, A. P. :
Mutations and phenotype in isolated glycerol kinase deficiency. Am. J. Hum. Genet. 58: 1205-1211, 1996.
PubMed ID : 8651297
13. Willard, H. F. :
Cloning of the X-linked glycerol kinase gene. Hum. Molec. Genet. 2: 95-96, 1993.
PubMed ID : 8499911
14. Zhang, Y.-H.; Dipple, K. M.; Vilain, E.; Huang, B.-L.; Finlayson, G.; Therrell, B. L.; Worley, K.; Deininger, P.; McCabe, E. R. B. :
AluY insertion (IVS4-52ins316alu) in the glycerol kinase gene from an individual with benign glycerol kinase deficiency. Hum. Mutat. 15: 316-323, 2000.
PubMed ID : 10737976

CREATION DATE

Cassandra L. Kniffin : 1/30/2004

EDIT HISTORY

terry : 12/17/2007
carol : 2/20/2004
carol : 2/20/2004
ckniffin : 2/5/2004

Copyright © 1966-2008 Johns Hopkins University

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