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Edward R B Mccabe - One of the best experts on this subject based on the ideXlab platform.
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gestational diabetes associated with a novel mutation 378 379instt in the Glycerol Kinase gene
Molecular genetics and metabolism reports, 2015Co-Authors: Yao H Zhang, Edward R B Mccabe, Johan L K Van Hove, Katrina M DippleAbstract:Glycerol Kinase Deficiency (GKD) is an X-linked inborn error of metabolism at the interface of fat and carbohydrate metabolism. We report a male patient with GKD and a novel insertion of TT in exon 5 at position 378 of the GK cDNA (378-379insTT). This resulted in a premature stop codon and 0.8% normal GK activity. The mother is a carrier for this mutation and had gestational diabetes requiring insulin during this pregnancy but not in her previous pregnancy. Given the association between GKD and type 2 diabetes mellitus, it is interesting that the mother had gestational diabetes while carrying an affected fetus. Therefore, GKD is another disease where there may be a maternal-fetal interaction based on genotype. Further investigations may help elucidate the role of GKD in the carrier mother's gestational diabetes. In addition, these studies will provide better-informed counseling to families with GKD regarding the risk to carrier females.
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Gestational diabetes associated with a novel mutation (378–379insTT) in the Glycerol Kinase gene
Elsevier, 2015Co-Authors: Yao H Zhang, Edward R B Mccabe, Johan L K Van Hove, Katrina M DippleAbstract:Glycerol Kinase Deficiency (GKD) is an X-linked inborn error of metabolism at the interface of fat and carbohydrate metabolism. We report a male patient with GKD and a novel insertion of TT in exon 5 at position 378 of the GK cDNA (378–379insTT). This resulted in a premature stop codon and 0.8% normal GK activity. The mother is a carrier for this mutation and had gestational diabetes requiring insulin during this pregnancy but not in her previous pregnancy. Given the association between GKD and type 2 diabetes mellitus, it is interesting that the mother had gestational diabetes while carrying an affected fetus. Therefore, GKD is another disease where there may be a maternal–fetal interaction based on genotype. Further investigations may help elucidate the role of GKD in the carrier mother's gestational diabetes. In addition, these studies will provide better-informed counseling to families with GKD regarding the risk to carrier females
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weighted gene co expression network analysis identifies biomarkers in Glycerol Kinase deficient mice
Molecular Genetics and Metabolism, 2009Co-Authors: Nicole K. Maclennan, Katrina M Dipple, Lola Rahib, Steve Horvath, Jun Dong, Jason E Aten, Loren Ornelas, Edward R B MccabeAbstract:Symptomatic Glycerol Kinase Deficiency (GKD) is associated with episodic metabolic and central nervous system deterioration. We report here the first application of weighted gene co-expression network analysis (WGCNA) to investigate a knockout (KO) murine model of a human genetic disease. WGCNA identified networks and key hub transcripts from liver mRNA of Glycerol Kinase (Gyk) KO and wild-type (WT) mice. Day of life 1 (dol1) samples from KO mice contained a network module enriched for organic acid metabolism before Gyk KO mice develop organic acidemia and die on dol3-4. Furthermore, the module containing Gyk was enriched with apoptotic genes. We used causal testing to elucidate the causal relationships between intramodular hub genes Acot, Psat and Plk3. Important causal relationships are confirmed in cell cultures. We provide evidence that GK may have an apoptotic moonlighting role that is lost in GKD. This first application of WGCNA to mouse knockout data provides insights into the molecular mechanisms of GKD pathogenesis. The resulting systems-genetic gene screening method identifies candidate biomarkers for GKD.
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deletion mapping in xp21 for patients with complex Glycerol Kinase Deficiency using snp mapping arrays
Human Mutation, 2007Co-Authors: Christopher M Stanczak, Yaohua Zhang, Zugen Chen, Stanley F Nelson, Edward R B MccabeAbstract:Infantile or complex Glycerol Kinase Deficiency (cGKD) is a contiguous gene deletion syndrome caused by a loss of GK (MIM# 300474), along with its neighboring genes, Duchenne muscular dystrophy (DMD; MIM# 300377) and/or Nuclear Receptor Subfamily 0, Group B, Member 1 (NR0B1; MIM# 300473). Patients with cGKD present with Glyceroluria and hyperGlycerolemia in association with DMD and/or adrenal hypoplasia congenita (AHC). The purpose of these investigations was to determine whether the Affymetrix GeneChip Mapping Array (SNP chip) could be utilized to detect and map breakpoints in patients with cGKD. Genomic DNAs from several primary lymphoblastoid cell lines from patients with cGKD were analyzed on the Affymetrix platform. The Affymetrix SNP chip is a high-density oligonucleotide array that allows a standardized, parallel interrogation of thousands of SNPs across the entire genome (except for the Y chromosome). Analysis of the array features' hybridization intensities enabled clear delineation of the patient deletions with a high degree of confidence. Many of these patient deletions had been mapped by PCR and their breakpoints confirmed by sequencing. This study demonstrates the utility of the Affymetrix Mapping GeneChips for molecular cytogenetic analysis, beyond the SNP genotyping for which the arrays were initially designed. With one out of 160 live births (approximately 25,000 U.S. neonates annually) reported to have cytogenetic disorders, we envision a significant need for such a standardized platform to carry out rapid, high-throughput, genomic analyses for molecular cytogenetics applications.
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asymptomatic isolated human Glycerol Kinase Deficiency associated with splice site mutations and nonsense mediated decay of mutant rna
Pediatric Research, 2006Co-Authors: Yaohua Zhang, Bingling Huang, Edward R B Mccabe, Ishwarlal Jialal, Hope Northrup, Katrina M DippleAbstract:Isolated Glycerol Kinase Deficiency (GKD) is an X-linked inborn error of metabolism that is either symptomatic or asymptomatic. GKD is due to deletions of, or mutations within, the GK gene, and there is no genotype-phenotype correlation. We identified three patients with asymptomatic GKD, determined that they had GK splice-site mutations, and studied the stability of their GK mRNA to understand the molecular mechanism of the GKD. All three patient mutations caused a frameshift and introduction of a premature stop codon. A fourth patient had an Alu insertion in intron 4 that led to alternative splicing. To study the effect of splice-site mutations on RNA species, we performed reverse transcriptase PCR and found only normal-sized products for all patients. Incubation with anisomycin to block nonsense-mediated decay (NMD), revealed two RNA species for each individual. 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. Normal RNA species observed in each patient are likely responsible for their mild phenotypes. We speculate that influences on RNA processing and protein stability represent modifiers of the GKD phenotype.
Katrina M Dipple - One of the best experts on this subject based on the ideXlab platform.
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gestational diabetes associated with a novel mutation 378 379instt in the Glycerol Kinase gene
Molecular genetics and metabolism reports, 2015Co-Authors: Yao H Zhang, Edward R B Mccabe, Johan L K Van Hove, Katrina M DippleAbstract:Glycerol Kinase Deficiency (GKD) is an X-linked inborn error of metabolism at the interface of fat and carbohydrate metabolism. We report a male patient with GKD and a novel insertion of TT in exon 5 at position 378 of the GK cDNA (378-379insTT). This resulted in a premature stop codon and 0.8% normal GK activity. The mother is a carrier for this mutation and had gestational diabetes requiring insulin during this pregnancy but not in her previous pregnancy. Given the association between GKD and type 2 diabetes mellitus, it is interesting that the mother had gestational diabetes while carrying an affected fetus. Therefore, GKD is another disease where there may be a maternal-fetal interaction based on genotype. Further investigations may help elucidate the role of GKD in the carrier mother's gestational diabetes. In addition, these studies will provide better-informed counseling to families with GKD regarding the risk to carrier females.
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Gestational diabetes associated with a novel mutation (378–379insTT) in the Glycerol Kinase gene
Elsevier, 2015Co-Authors: Yao H Zhang, Edward R B Mccabe, Johan L K Van Hove, Katrina M DippleAbstract:Glycerol Kinase Deficiency (GKD) is an X-linked inborn error of metabolism at the interface of fat and carbohydrate metabolism. We report a male patient with GKD and a novel insertion of TT in exon 5 at position 378 of the GK cDNA (378–379insTT). This resulted in a premature stop codon and 0.8% normal GK activity. The mother is a carrier for this mutation and had gestational diabetes requiring insulin during this pregnancy but not in her previous pregnancy. Given the association between GKD and type 2 diabetes mellitus, it is interesting that the mother had gestational diabetes while carrying an affected fetus. Therefore, GKD is another disease where there may be a maternal–fetal interaction based on genotype. Further investigations may help elucidate the role of GKD in the carrier mother's gestational diabetes. In addition, these studies will provide better-informed counseling to families with GKD regarding the risk to carrier females
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disruption of Glycerol metabolism by rnai targeting of genes encoding Glycerol Kinase results in a range of phenotype severity in drosophila
PLOS ONE, 2013Co-Authors: Patrick J. Wightman, George R. Jackson, Katrina M DippleAbstract:In Drosophila, RNAi targeting of either dGyk or dGK can result in two alternative phenotypes: adult Glycerol hypersensitivity or larval lethality. Here we compare these two phenotypes at the level of Glycerol Kinase (GK) phosphorylation activity, dGyk and dGK-RNA expression, and Glycerol levels. We found both phenotypes exhibit reduced but similar levels of GK phosphorylation activity. Reduced RNA expression levels of dGyk and dGK corresponded with RNAi progeny that developed into Glycerol hypersensitive adult flies. However, quantification of dGyk/dGK expression levels for the larval lethality phenotype revealed unexpected levels possibly due to a compensatory mechanism between dGyk and dGK or RNAi inhibition. The enzymatic role of Glycerol Kinase converts Glycerol to Glycerol 3-phosphate. As expected, elevated Glycerol levels were observed in larvae that went on to develop into Glycerol hypersensitive adults. Interestingly, larvae that died before eclosion revealed extremely low Glycerol levels. Further characterization identified a wing phenotype that is enhanced by a dGpdh null mutation, indicating disrupted Glycerol metabolism underlies the wing phenotype. In humans, Glycerol Kinase Deficiency (GKD) exhibits a wide range of phenotypic variation with no obvious genotype-phenotype correlations. Additionally, disease severity often does not correlate with GK phosphorylation activity. It is intriguing that both human GKD patients and our GKD Drosophila model show a range of phenotype severity. Additionally, the lack of correlation between GK phosphorylation and dGyk/dGK-RNA expression with phenotypic severity suggests further study including understanding the alternative functions of the GK protein, could provide insights into the complex pathogenic mechanism observed in human GKD patients.
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Glycerol Hypersensitivity in a Drosophila Model for Glycerol Kinase Deficiency Is Affected by Mutations in Eye Pigmentation Genes
PloS one, 2012Co-Authors: Patrick J. Wightman, George R. Jackson, Katrina M DippleAbstract:Glycerol Kinase plays a critical role in metabolism by converting Glycerol to Glycerol 3-phosphate in an ATP dependent reaction. In humans, Glycerol Kinase Deficiency results in a wide range of phenotypic variability; patients can have severe metabolic and CNS abnormalities, while others possess hyperGlycerolemia and Glyceroluria with no other apparent phenotype. In an effort to help understand the pathogenic mechanisms underlying the phenotypic variation, we have created a Drosophila model for Glycerol Kinase Deficiency by RNAi targeting of dGyk (CG18374) and dGK (CG7995). As expected, RNAi flies have reduced Glycerol Kinase RNA expression, reduced phosphorylation activity and elevated Glycerol levels. Further investigation revealed these flies to be hypersensitive to fly food supplemented with Glycerol. Due to the hygroscopic nature of Glycerol, we predict Glycerol hypersensitivity is a result of greater susceptibility to desiccation, suggesting Glycerol Kinase to play an important role in desiccation resistance in insects. To evaluate a role for genetic modifier loci in determining severity of the Glycerol hypersensitivity observed in knockdown flies, we performed a preliminary screen of lethal transposon insertion mutant flies using a Glycerol hypersensitive survivorship assay. We demonstrate that this type of screen can identify both enhancer and suppressor genetic loci of Glycerol hypersensitivity. Furthermore, we found that the Glycerol hypersensitivity phenotype can be enhanced or suppressed by null mutations in eye pigmentation genes. Taken together, our data suggest proteins encoded by eye pigmentation genes play an important role in desiccation resistance and that eye pigmentation genes are strong modifiers of the Glycerol hypersensitive phenotype identified in our Drosophila model for Glycerol Kinase Deficiency.
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weighted gene co expression network analysis identifies biomarkers in Glycerol Kinase deficient mice
Molecular Genetics and Metabolism, 2009Co-Authors: Nicole K. Maclennan, Katrina M Dipple, Lola Rahib, Steve Horvath, Jun Dong, Jason E Aten, Loren Ornelas, Edward R B MccabeAbstract:Symptomatic Glycerol Kinase Deficiency (GKD) is associated with episodic metabolic and central nervous system deterioration. We report here the first application of weighted gene co-expression network analysis (WGCNA) to investigate a knockout (KO) murine model of a human genetic disease. WGCNA identified networks and key hub transcripts from liver mRNA of Glycerol Kinase (Gyk) KO and wild-type (WT) mice. Day of life 1 (dol1) samples from KO mice contained a network module enriched for organic acid metabolism before Gyk KO mice develop organic acidemia and die on dol3-4. Furthermore, the module containing Gyk was enriched with apoptotic genes. We used causal testing to elucidate the causal relationships between intramodular hub genes Acot, Psat and Plk3. Important causal relationships are confirmed in cell cultures. We provide evidence that GK may have an apoptotic moonlighting role that is lost in GKD. This first application of WGCNA to mouse knockout data provides insights into the molecular mechanisms of GKD pathogenesis. The resulting systems-genetic gene screening method identifies candidate biomarkers for GKD.
Wolfgang G. Sippell - One of the best experts on this subject based on the ideXlab platform.
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Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society Congenital Adrenal Hypoplasia: Clinical Spectrum, Experience with Hormonal Diagnosis, and Report on New Point Mutations of the DAX-1 Gene
2013Co-Authors: Michael Peter, Matthias Viemann, Carl-joachim Partsch, Wolfgang G. SippellAbstract:X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with Glycerol Kinase Deficiency (GKD) and Duchenne’s muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne’s muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates’ persisting fetocortex. Aldosterone Deficiency usually preceded cortisol Deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. A
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Multiplex ligation-dependent probe amplification analysis of the NR0B1(DAX1) locus enables explanation of phenotypic differences in patients with X-linked congenital adrenal hypoplasia.
Hormone Research in Paediatrics, 2012Co-Authors: Michela Barbaro, Andrea Haake, Jürgen Brämswig, Juan Pedro López-siguero, Udo Menken, Michael Peter, Susanne Bens, Paul-martin Holterhus, Wolfgang G. SippellAbstract:Background/Aim:X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadic hypogonadism. It is caused by deletions or point mutations of the NR0B1 gene, on Xp21. AHC can be associated with Glycerol Kinase Deficiency, Duchenne muscular dystrophy and mental retardation (MR), as part of a contiguous gene deletion syndrome. A synthetic probe set for multiplex ligation-dependent probe amplification analysis was developed to confirm and characterize NR0B1 deletions in patients with AHC and to correlate their genotypes with their divergent phenotypes. Results:In 2 patients, isolated AHC was confirmed, while a patient at risk for metabolic crisis was revealed as the deletion extends to the GK gene. A deletion extending to IL1RAPL1 was confirmed in both patients showing MR. Thus, a good genotype-phenotype correlation was confirmed. Conclusions:Multiplex ligation-dependent probe amplification analysis is a valuable tool to detect NR0B1 and contiguous gene deletions in patients with AHC. It is especially helpful for IL1RAPL1 deletion detection as no clinical markers for MR are available. Furthermore, multiplex ligation-dependent probe amplification has the advantage to identify female carriers that, depending on the deletion extension, have a high risk of giving birth to children with MR, AHC, Glycerol Kinase Deficiency and Duchenne muscular dystrophy.
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congenital adrenal hypoplasia clinical spectrum experience with hormonal diagnosis and report on new point mutations of the dax 1 gene
The Journal of Clinical Endocrinology and Metabolism, 1998Co-Authors: Michael Peter, Matthias Viemann, Carl-joachim Partsch, Wolfgang G. SippellAbstract:X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with Glycerol Kinase Deficiency (GKD) and Duchenne's muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne's muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates' persisting fetocortex. Aldosterone Deficiency usually preceded cortisol Deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. An ACTH test was often necessary to detect cortisol Deficiency in the very young infants. In some patients, serial testing was necessary to establish the correct diagnosis. In 4 boys studied during the first 3 months after birth, we found pubertal LH, FSH, and testosterone plasma levels indicating postnatal transient activation of the hypothalamic-pituitary-gonadal axis as in normal boys. Previous studies have shown that the DAX-1 gene is deleted in the AHC patients with a contiguous gene syndrome and is mutated in nondeletion patients. Most of the point mutations identified in AHC patients were frameshift mutations and stop mutations. In the 15 patients available for molecular analysis of the DAX-1 gene, there were large deletions in 6 patients and point mutations in another 7 patients. All of the point mutations identified in the present study resulted in a nonfunctional truncated DAX-1 protein. Two brothers with primary adrenal insufficiency and a medical history that strongly suggested AHC had no mutation in the DAX-1 gene. Thus, additional, as yet unknown genes must play a part in normal adrenal cortical development.
S Salisbury - One of the best experts on this subject based on the ideXlab platform.
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congenital adrenal hypoplasia duchenne muscular dystrophy and Glycerol Kinase Deficiency importance of laboratory investigations in delineating a contiguous gene deletion syndrome
Clinical Chemistry, 1994Co-Authors: D E Cole, W. K. Seltzer, L A Clarke, D C Riddell, K A Samson, S SalisburyAbstract:We describe an infant with adrenal insufficiency who was subsequently diagnosed with Duchenne muscular dystrophy (DMD) and hyperGlycerolemia due to Glycerol Kinase Deficiency. Karyotyping showed a deletion on the short arm of the X chromosome (p21.1 to p22.1). Molecular mapping revealed that the deletion extended from the 3' end of the DMD gene to a site telomeric to the loci for X-linked congenital adrenal hypoplasia and Glycerol Kinase Deficiency. These results are diagnostic for an Xp21 contiguous gene deletion syndrome--so named because the deletion manifests as a distinctive cluster of otherwise unrelated single-gene disorders in the same individual. The Xp21 syndrome should be considered in any infant with adrenal insufficiency. Measurement of serum triglycerides (without Glycerol blanking) and creatine Kinase activity are simple screening tests that may facilitate early diagnosis and appropriate genetic counseling about risks of recurrence in subsequent offspring.
Ann P. Walker - One of the best experts on this subject based on the ideXlab platform.
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mutations and phenotype in isolated Glycerol Kinase Deficiency
American Journal of Human Genetics, 1996Co-Authors: Ann P. Walker, Françoise Muscatelli, Niklas Dahl, Jamel Chelly, A N Stafford, H K Blomquist, J Delanghe, P Willems, B Steinmann, Anthony P. MonacoAbstract:We demonstrate that isolated Glycerol Kinase (GK) Deficiency in three families results from mutation of the Xp21 GK gene. GK mutations were detected in four patients with widely differing phenotypes. Patient 1 had a splice-site mutation causing premature termination. His general health was good despite absent GK activity, indicating that isolated GK Deficiency can be silent. Patient 2 had GK Deficiency and a severe phenotype involving psychomotor retardation and growth delay, bone dysplasia, and seizures, similar to the severe phenotype of one of the first described cases of GK Deficiency. His younger brother, patient 3, also had GK Deficiency, but so far his development has been normal. GK exon 17 was deleted in both brothers, implicating additional factors in causation of the severe phenotype of patient 2. Patient 4 had both GK Deficiency with mental retardation and a GK missense mutation (D440V). Possible explanations for the phenotypic variation of these four patients include ascertainment bias; metabolic or environmental stress as a precipitating factor in revealing GK-related changes, as has 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.
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mutations in the dax 1 gene give rise to both x linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism
Nature, 1994Co-Authors: Françoise Muscatelli, Ann P. Walker, D Recan, Tim M Strom, Elena Zanaria, Alfons Meindl, Barbara Bardoni, Silvana Guioli, Gunther Zehetner, Wolfgang RablAbstract:ADRENAL hypoplasia congenita (AHC) is an X-linked disorder characterized by primary adrenal insufficiency1,2. Hypogonadotropic hypogonadism (HHG) is frequently associated with this disorder but is thought not to be caused by the low adrenal androgen levels due to adrenal hypoplasia3,4. It is uncertain whether there are two distinct yet physically linked genes responsible for AHC and HHG or a single gene responsible for both diseases. AHC can occur as a part of a contiguous deletion syndrome together with Duchenne muscular dystrophy (DMD) and/or Glycerol Kinase Deficiency (GKD). From the analysis of deletions, the following gene order has been deduced: Xpter-AHC-GKD-DMD-cen5,6. An AHC critical region of 200–500 kilobases has been defined by physical mapping7,8 and partially overlaps with a 160-kilobase dosage-sensitive sex (DSS) reversal critical region9. The DAX-1 (DSS-AHC critical region on the X, gene 1) gene was isolated and found to encode a new member of the nuclear hormone receptor family10. Here we report that DAX-1 is deleted in 14 patients and point mutations were found in the coding region in DNA from 12 unrelated individuals. All AHC patients over 14 years old and with only point mutations in DAX-1 were also diagnosed with HHG, confirming that the DAX-1 gene is responsible for both X-linked AHC and HHG. But in four sporadic cases and a single familial case, no point mutations were found, suggesting genetic heterogeneity or differential expression of DAX-1.
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Isolation of the human Xp21 Glycerol Kinase gene by positional cloning
Human molecular genetics, 1993Co-Authors: Ann P. Walker, Françoise Muscatelli, Anthony P. MonacoAbstract:The gene for human Glycerol Kinase Deficiency (GK) maps in Xp21.3 in a critical region of about 50-250 kb located distal to the Duchenne muscular dystrophy gene (DMD) by analysis of patient deletions and YAC contigs. We have used a genomic exon amplification strategy to isolate potential exons from two cosmids which mapped to this interval. The genomic exons were used to isolate six overlapping cDNA clones from human fetal liver which encode the X-linked Glycerol Kinase gene. The cDNA clones map to cosmids, YAC clones and deletions in patients which define the GK critical region and also hybridize to several autosomal fragments and one Xq fragment in genomic DNA. The GK gene is expressed most in human liver with three transcript sizes of 1.85, 2.7, and 3.7 kb. Sequence analysis of 1.5 kb of several overlapping liver cDNA clones predicted a protein with approximately 63% similarity to the E. coli and B. subtilis Glycerol Kinase genes. The liver cDNA clones have sequence identity with four genomic exons and the 3' untranslated region from an Xp21.3 cosmid thus indicating that this is the expressed GK gene which when deleted in patients gives rises to GK Deficiency.
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a yac contig in xp21 containing the adrenal hypoplasia congenita and Glycerol Kinase Deficiency genes
Human Molecular Genetics, 1992Co-Authors: Ann P. Walker, Jamel Chelly, Donald R Love, Yumiko Ishikawa Brush, D Recan, Jeanlouis Chaussain, Christine Oley, Michael J Connor, John R W Yates, D A PriceAbstract: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. 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. A pulsed-field gel electrophoresis map of the YAC contig identified 3 potential CpG islands. Whole YAC hybridization identified cosmids both for construction of cosmid contigs, and isolation of single copy probes. Thirteen new single copy probes and DXS28 and DXS708 were hybridized on a panel of patients; the deletion mapping indicates that the YAC contig contains both GK and at least part of AHC, and together with the physical map defines a GK critical region of 50-250 kb. In one AHC patient with a cytogenetically detectable deletion we used the new probes to characterize a complex double deletion. Non-overlapping deletions observed in other unrelated AHC patients indicate that the AHC gene is large, extending over at least 200-500 kb. This mapping provides the basis for the identification of the AHC and GK genes.