Molecular characterization of six new cases of red blood cell hexokinase deficiency yields four novel mutations in HK1

Kořalková, Pavla; Mojzíková, Renata; Oirschot, B. van; Macartney, Christine; Timr, Pavel; Corrons, Joan Lluís Vives i; Laluhova, Zuzana Striezencova; Lejhancová, Kateřina; Divoký, Vladimír; Wijk, Richard van

doi:10.1016/j.bcmd.2016.04.002

Cited by 10 publications

(21 citation statements)

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“…We determined the kinetic properties of red blood cell hexokinase in two patients (c.1252A>G, p.(Lys418Glu) and c.1334C>T, p.(Ser445Leu)) using previously described methods [14] and found no difference between control and patient samples in the affinity of mutant HK for glucose or ATP, nor was there any difference in thermal stability of these two variants (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

“…4. The most common clinical phenotype associated with HK1 variants is nonspherocytic hemolytic anemia (OMIM #235700) caused by bi-allelic variants affecting the hexokinase activity [3,4,14,23,24]. Homozygous variants in the 5' UTR of HK1 have been associated with hereditary motor and sensory neuropathy, Russe Type (OMIM #605285) [5,6,25].…”

Section: Discussionmentioning

confidence: 99%

“…Goebel et al [31] Gilsanz et al [32] Magnani et al [33] Kanno et al [3] Koralkova et al [14] Hemolytic anemia + + + + +…”

Section: Publicationmentioning

confidence: 99%

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De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment

Okur

Cho²,

Wijk

et al. 2019

Eur J Hum Genet

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Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Hexokinase activity in red blood cells of two patients was normal, suggesting that the disease mechanism is not due to loss of hexokinase enzymatic activity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment

Okur

Cho²,

Wijk

et al. 2019

Eur J Hum Genet

Self Cite

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“…Fetal death has been reported in one case (Kanno et al , ). Although approximately 30 cases of HK deficiency have been reported, molecular findings have been described in only 11 patients (Khazal et al , ; Koralkova et al , ). Definitive diagnosis requires biochemical testing of enzyme levels and/or genetic testing, which are often difficult and not readily available.…”

mentioning

confidence: 99%

A nonsense variant in the Hexokinase 1 gene (HK1) causing severe non‐spherocytic haemolytic anaemia: genetic analysis exemplifies ambiguity due to multiple Isoforms

et al. 2019

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“…They are totally reliant on the hexokinase reaction and glycolysis plus the pentose shunt pathway to satisfy their energetic, redox, and functional demands to carry oxygen to all organs of the body. Mutations that cause hexokinase deficiency are very rare and have the primary clinical manifestation of hemolytic anemia [100] that is evident in patients in whom red cell HK activity is reduced by 25-50%; HK activity is lowered similarly in platelets and lymphocytes [146][147][148][149]. Severity of symptoms can vary because lower Glc-6-P levels reduce its inhibition of HK so a higher flux can be maintained.…”

Section: Red Cellsmentioning

confidence: 99%

Hypothesis: A Novel Neuroprotective Role for Glucose-6-phosphatase (G6PC3) in Brain—To Maintain Energy-Dependent Functions Including Cognitive Processes

Dienel

2020

Neurochem Res

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The isoform of glucose-6-phosphatase in liver, G6PC1, has a major role in whole-body glucose homeostasis, whereas G6PC3 is widely distributed among organs but has poorly-understood functions. A recent, elegant analysis of neutrophil dysfunction in G6PC3-deficient patients revealed G6PC3 is a neutrophil metabolite repair enzyme that hydrolyzes 1,5-anhydroglucitol-6-phosphate, a toxic metabolite derived from a glucose analog present in food. These patients exhibit a spectrum of phenotypic characteristics and some have learning disabilities, revealing a potential linkage between cognitive processes and G6PC3 activity. Previously-debated and discounted functions for brain G6PC3 include causing an ATP-consuming futile cycle that interferes with metabolic brain imaging assays and a nutritional role involving astrocyte-neuron glucose-lactate trafficking. Detailed analysis of the anhydroglucitol literature reveals that it competes with glucose for transport into brain, is present in human cerebrospinal fluid, and is phosphorylated by hexokinase. Anhydroglucitol-6-phosphate is present in rodent brain and other organs where its accumulation can inhibit hexokinase by competition with ATP. Calculated hexokinase inhibition indicates that energetics of brain and erythrocytes would be more adversely affected by anhydroglucitol-6-phosphate accumulation than heart. These findings strongly support the paradigm-shifting hypothesis that brain G6PC3 removes a toxic metabolite, thereby maintaining brain glucose metabolism-and ATP-dependent functions, including cognitive processes.

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Molecular characterization of six new cases of red blood cell hexokinase deficiency yields four novel mutations in HK1

Cited by 10 publications

References 20 publications

De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment

De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment

A nonsense variant in the Hexokinase 1 gene (HK1) causing severe non‐spherocytic haemolytic anaemia: genetic analysis exemplifies ambiguity due to multiple Isoforms

Hypothesis: A Novel Neuroprotective Role for Glucose-6-phosphatase (G6PC3) in Brain—To Maintain Energy-Dependent Functions Including Cognitive Processes

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