Human glycerol kinase deficiency with hyperglycerolemia and glyceroluria

McCabe, Edward R.B.; Fennessey, Paul V.; Guggenheim, Mary Anne; Miles, Barbara S.; Bullen, William W.; Sceats, Donald J.; Goodman, Stephen I.

doi:10.1016/0006-291x(77)91437-1

Cited by 70 publications

(24 citation statements)

References 8 publications

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“…Glycerol 'toxi city' (i.e. lethargy, vomiting, loss of con sciousness and sometimes retardation) has been reported in a number of young patients with unidentified metabolic disorders [Mc Laren et al, 1975], with fructose-1,6-diphos- [Greene et al, 1972], with multiple liver enzyme deficiencies [Wapnir et , 1982], and with the infantile and juvenile rms of glycerol kinase deficiency [McCabe al., 1977;McCabe, 1983;Ginns et al, '84], Although the mechanism of the CNS ixicity is unknown, many of the patients ive fewer symptoms when they are fed a ycerol-free, low-fat diet [Greene et al, >72;McLaren et al, 1975;Wapnir et al, >82: Ginns et al. 1984], There must be some potential for acumulating unacceptable concentrations of lycerol in normal brain tissue if the ability to oiidize large amounts of glycerol is a detoxfication mechanism.…”

Section: Discussionmentioning

confidence: 99%

A Developmental Study of Glycerol Oxidation by Rat Brain

Mc¹,

Mm²,

Jt³

1986

Dev Neurosci

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The rates of oxidation of several concentrations of [1,3–¹⁴C]glycerol to ¹⁴CO₂were measured in whole homogenates of brain from rats of different ages. The rates of oxidation of glycerol at concentrations from 0.1 to 20 mM were significantly lower with brains of neonatal animals than with adult rats, and increased to adult levels during the second to third week of life. The addition of unlabelled glucose decreased the rate of [1,3–¹⁴C]glycerol oxidation by about 40% at all ages and glycerol concentrations. Increasing the initial concentration of glycerol 200-fold from 0.1 to 20 mM resulted in more than a 100-fold increase in the rate of glycerol oxidation. This pattern of an increased rate of oxidation with increasing substrate concentration was in marked contrast to that previously found with other brain energy substrates which levelled off with increasing concentration. The data suggest that glycerol could be an important energy substrate in certain areas or cell types in adult rat brain, or that the ability to oxidize high concentrations of glycerol is a detoxification mechanism to prevent accumulation of excess free glycerol.

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Section: Discussionmentioning

confidence: 99%

A Developmental Study of Glycerol Oxidation by Rat Brain

Mc¹,

Mm²,

Jt³

1986

Dev Neurosci

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“…GK activity was determined by using a radiolabel assay reported previously [20]. Two biological samples of each cell line were assayed in duplicate with 2 μg and 4 μg of total cellular protein for 20 min, assay conditions previously determined by us to be optimal for H4IIE cells (data not shown).…”

Section: Gk Activity Assaymentioning

confidence: 99%

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

Sriram

Rahib

et al. 2008

Molecular Genetics and Metabolism

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Glycerol kinase has several diverse activities in mammalian cells. Glycerol kinase deficiency is a complex, single-gene, inborn error of metabolism wherein no genotype-phenotype correlation has been established. Since glycerol kinase has been suggested to exhibit additional activities than glycerol phosphorylation, expression level perturbation in this enzyme may affect cellular physiology globally. To investigate this possibility, we conducted metabolic investigations of wild type and two glycerol kinase-overexpressing H4IIE rat hepatoma cell lines constructed in this study. The glycerol kinase-overexpressing cell lines exhibited a significantly higher consumption of carbon sources per cell, suggesting excess carbon expenditure. Furthermore, we quantified intracellular metabolic fluxes by employing stable isotope ( 13 C) labeling with a mathematically designed substrate mixture, gas chromatography-mass spectrometry, and comprehensive isotopomer balancing. This flux analysis revealed that the pentose phosphate pathway flux in the glycerol kinase-overexpressing cell lines was two-fold higher than that in the wild type, in addition to subtler flux changes in other pathways of carbohydrate metabolism. Furthermore, the activity and transcript level of the lipogenic enzyme glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the pentose phosphate pathway, were also about two-fold higher than that of the wild type; these data corroborate the flux analysis results. This study shows that glycerol kinase affects carbon metabolism globally, possibly through its additional functions, and highlights glycerol kinase's multifaceted role in cellular physiology.

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“…X-linked cytomegalic AHC was mapped to the Xp21 region by deletion patients with co-morbidities of Duchenne muscular dystrophy, glycerol kinase deficiency, and mental retardation [McCabe et al, 1977;Guggenheim et al, 1980;Bartley et al, 1982;Bartley et al, 1986]. Positional cloning led to the identification of the NR0B1 gene Guo et al, 1995b], and to the demonstration that X-linked AHC with HH results from intragenic mutations Zanaria et al, 1994;Guo et al, 1995b].…”

Section: Introductionmentioning

confidence: 98%

Mutations inNR0B1 (DAX1) andNR5A1 (SF1) responsible for adrenal hypoplasia congenita

2001

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Adrenal hypoplasia congenita (AHC) causes primary adrenal insufficiency due to the failure of development of the adrenal cortex. Clinical and pedigree data indicate that the condition is genetically heterogeneous. The predominant adrenal hypoplasia congenita locus, however, is the NR0B1 gene, at Xp21, encoding the protein DAX1. In this article, we present a compendium of published NR0B1 mutations and polymorphisms, and discuss them in the contexts of known biology and clinical applicability. The recent descriptions of patients with primary adrenal insufficiency due to mutations of NR5A1, which encodes SF1, are also discussed.

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Human glycerol kinase deficiency with hyperglycerolemia and glyceroluria

Cited by 70 publications

References 8 publications

A Developmental Study of Glycerol Oxidation by Rat Brain

A Developmental Study of Glycerol Oxidation by Rat Brain

Global metabolic effects of glycerol kinase overexpression in rat hepatoma cells

Mutations inNR0B1 (DAX1) andNR5A1 (SF1) responsible for adrenal hypoplasia congenita

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