HGNC Approved Gene Symbol: HK1
SNOMEDCT: 715799004;
Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:69,270,000-69,401,882 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.1 | Hemolytic anemia due to hexokinase deficiency | 235700 | Autosomal recessive | 3 |
| Neurodevelopmental disorder with visual defects and brain anomalies | 618547 | Autosomal dominant | 3 | |
| Neuropathy, hereditary motor and sensory, Russe type | 605285 | Autosomal recessive | 3 | |
| Retinitis pigmentosa 79 | 617460 | Autosomal dominant | 3 |
Hexokinase (EC 2.7.1.1) catalyzes the first step in glucose metabolism, using ATP for the phosphorylation of glucose to glucose-6-phosphate. Four different forms of hexokinase, designated type HK1, HK2 (601125), HK3 (142570), and HK4 (138079), encoded by different genes, are present in mammalian tissues. Among these, HK1 is the predominant glucose phosphorylating activity in those tissues that share a strict dependence on glucose utilization for their physiologic functions, such as brain, erythrocytes, platelets, lymphocytes, and fibroblasts (summary by Bianchi et al., 1997). Different isoforms of HK1 are either cytoplasmic or associated with the outer mitochondrial membrane (OMM) through a 5-prime porin (VDAC1; 604492)-binding domain (Murakami and Piomelli, 1997).
Nishi et al. (1988) analyzed cDNA clones encoding human hexokinase isolated from an adult kidney library. Analysis of this 917-amino acid protein showed that the sequences of the N- and C-terminal halves, corresponding to the regulatory and catalytic domains, respectively, are homologous. Eukaryotic hexokinases evolved from duplication of a gene encoding a protein of about 450 amino acids. Griffin et al. (1991) thought that comparisons of sequences in many species supported the theory of Ureta (1982) that the mammalian hexokinases arose from the duplication and fusion of an ancestral protoenzyme and that the yeast and mammalian glucokinases arose twice in evolution. Sequence analysis demonstrated that a 15-amino acid porin-binding domain in the N terminus of HK1 is absolutely conserved and mediates the binding of HK1 to the mitochondria. In the course of their work, Griffin et al. (1991) developed a method for cloning the cDNA for a low abundance protein using knowledge of the evolutionary conservation of amino acid and nucleotide sequence.
By liquid chromatography, Murakami et al. (1990) identified 2 distinct major isozymes of human red blood cell (RBC) hexokinase. One had a molecular mass similar to that of HK1 identified in liver, and the other, designated HKR, was larger than HK1 by several kilodaltons. RBC from normal blood contained HK1 and HKR at an equal activity, but in reticulocyte-rich RBC, HKR dominated. Murakami and Piomelli (1997) isolated a cDNA clone for the red cell-specific HK isozyme HKR. Its nucleotide sequence was identical to HK1 cDNA except for the 5-prime end. It lacks the first 62 nucleotides of the HK1 coding region; instead, it contains a unique sequence of 60 nucleotides at the beginning of the coding sequence as well as another unique sequence upstream of the putative translation initiation site. It lacks the porin-binding domain that facilitates binding to mitochondria, thus explaining the exclusive cytoplasmic localization of red blood cell HK. Northern blot analysis showed that it was expressed in reticulocytes and in an erythroleukemic cell line, but not in a lymphocytic cell line.
Mori et al. (1996) reported the cloning of cDNAs representing 3 unique human type 1 hexokinase mRNAs expressed in testis, which were not detected by Northern blot analysis in other human tissues. These mRNAs contained unique sequences in the 5-prime terminus and lacked the porin-binding domain (PBD), a conserved sequence that mediates the binding of hexokinase to the mitochondria. The sequences were similar to those identified by Mori et al. (1993) in mouse testis.
Amendola et al. (2019) reported a direct, GTP-dependent interaction between the KRAS exon 4A-specific isoform KRAS4A (see 190070) and HK1 that alters the activity of the kinase, and thereby established that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.
Ruzzo et al. (1998) determined that the HK1 gene contains 18 exons and spans about 75 kb. Analysis of the 5-prime flanking region revealed binding sites for AP1 and CRE as well as several binding sites for SP1. Ruzzo et al. (1998) identified an exon 1 specific to HK1 expressed in somatic cells; an alternative exon (exon 1R) transcribed in red blood cells replaced the somatic exon 1 by alternative splicing. Exon 1R lacks the porin-binding domain.
Andreoni et al. (2000) found that multiple testis-specific HK1 transcripts are encoded by 6 different exons; 5 of the exons are located upstream from the somatic exon 1, and one is located within intron 1. With identification of these additional exons, they determined that the gene spans at least 100 kb.
Shows (1974) presented evidence from somatic cell hybrid experiments that hexokinase and cytoplasmic glutamate oxaloacetic transaminase are syntenic on chromosome 10. By gene dosage studies of fibroblasts, Gitelman and Simpson (1982) mapped HK1 to 10p11-q23. By dosage effect, Dallapiccola et al. (1981) narrowed the HK1 assignment to 10pter-p13. Dallapiccola et al. (1984) determined HK1 activity in the red cells of 5 patients with various partial duplications of 10p and concluded that the most likely regional assignment for HK1 is 10p11.2. By in situ hybridization, Shows et al. (1989) regionalized the HK1 gene to 10q22. Daniele et al. (1992) used an HK1 cDNA as a probe for the study of a panel of human-hamster somatic cell hybrids to assign the gene to the long arm of chromosome 10 in the region q11.2-qter. This result agrees with those reported by Gitelman and Simpson (1982) and Shows et al. (1989) but conflicts with that reported by Dallapiccola et al. (1984). Daniele et al. (1992) acknowledged the possibility that the HK1 probe they used recognized more than a single locus but concluded that if 2 or more HK loci exist they are all located on chromosome 10. Gelb et al. (1992) demonstrated that most of the coding region of the HK1 gene is located in a 120-kb YAC, which mapped entirely to chromosome 10.
The genes for 3 separate hexokinases have been assigned to specific sites as of 1997: HK1, a red-cell isoform, to chromosome 10; HK2 (601125), the major hexokinase expressed in skeletal muscle, to chromosome 2; and HK3 (142570), an isoform in white blood cells, to chromosome 5. Hexokinase-4 (HK4) is glucokinase (GCK; 138079), which maps to chromosome 7.
Nonspherocytic Hemolytic Anemia Due to Hexokinase Deficiency
Bianchi and Magnani (1995) reported the molecular characterization of the defect in HK1 in a patient with hemolytic anemia due to hexokinase deficiency (235700). PCR amplification and sequence of the cDNA revealed compound heterozygosity for a deletion and a single nucleotide substitution. The 96-bp deletion (142600.0001) involved nucleotides 577 to 672 of their cDNA sequence and was found in the cDNA of none of 14 unrelated normal subjects. The sequence of the HK1 allele without deletion showed a T-to-C transition of nucleotide 1677, which caused the amino acid change leu529-to-ser (142600.0002). The substitution was not found in 10 normal controls. Bianchi and Magnani (1995) stated that to their knowledge only 14 cases had been described, 2 of which had been studied in their laboratory: HK-Melzo and HK-Napoli. It was in HK-Melzo that the molecular defect was demonstrated. They showed that in the HK-Melzo variant, the HK deficiency was expressed not only in erythrocytes but also in platelets, lymphocytes, and fibroblasts. All these types of cells contain HK type I as the predominant glucose phosphorylating enzyme and, in particular, platelets and erythrocytes share a strict dependence upon glucose utilization for their physiologic functions.
In a girl, born of consanguineous parents, with severe nonspherocytic hemolytic anemia due to hexokinase deficiency previously reported by Rijksen et al. (1983), van Wijk et al. (2003) identified a homozygous mutation in the HK1 gene (T680S; 142600.0004). The mutation, which segregated with the disorder in the family and was not found in 50 controls, was designated 'Utrecht.' In vitro studies of the mutant enzyme showed that it had a 2-fold decrease in affinity for Mg-ATP2 and a markedly decreased affinity for the inhibitor glucose-1,6-diphosphate. Patient red cells and platelets had about 25% residual activity.
Russe Type of Hereditary Motor and Sensory Neuropathy
In all 34 European Gypsy individuals with the Russe type of hereditary motor and sensory neuropathy (HMSNR; 605285) who were studied, Hantke et al. (2009) identified a homozygous sequence change in the HK1 gene (142600.0003) that mapped within the candidate disease interval on chromosome 10q. The mutation was located at a highly conserved nucleotide in the putative AltT2 exon located in the 5-prime region upstream of HK1. The variant was found in heterozygous state in 5 of 790 control individuals representing a cross-section of the Gypsy population, but not in 233 Bulgarian controls. AltT2-containing transcripts in the mouse peripheral nerve were rare compared to the coding region of HK1. However, 6 of 8 testis AltT2-containing isoforms were found, with expression patterns differing between the peripheral nerve and the brain and between newborn and adult tissues in mice. There was no difference in HK1 mRNA in Schwann cells derived from patients or controls, and patient cells showed no evidence of HK1 enzyme activity compared to controls. Bioinformatic tools did not suggest an effect of the variant on HK1 gene splicing or binding sites for interacting proteins. However, there was evidence that the variant may cause a ter-to-tyr substitution in 1 upstream open reading frame that had a non-AUG start codon, which could potentially disrupt HK1 translation regulation. Hantke et al. (2009) speculated that non-OMM-binding HK1 may play a role in the pathogenesis of HMSNR.
Sevilla et al. (2013) found that 11 patients from 9 Roma Gypsy families were homozygous for the HK1 variant (g.9712G-C; 142600.0003) identified by Hantke et al. (2009). Haplotype analysis confirmed a founder effect in this population.
Retinitis Pigmentosa 79
In affected individuals from 5 families (UTAD003, UTAD936, UTAD952, MOGL1, and MOGL2) segregating autosomal dominant retinitis pigmentosa (RP79; 617460), Sullivan et al. (2014) identified heterozygosity for a missense mutation in the HK1 gene (E847K; 142600.0005) that segregated fully with disease in each family and was not found in public variant databases. None of the patients had extraocular manifestations and no systemic abnormalities in glycolysis were detected, even in 1 patient who was homozygous for the mutation. Sullivan et al. (2014) noted that the mutation is located outside the catalytic domains and suggested that the effect of the mutation was limited to the retina.
In affected individuals from a large 4-generation family of northern European ancestry with RP, Wang et al. (2014) identified heterozygosity for the E847K mutation in the HK1 gene. Affected individuals showed no signs of anemia, exercise intolerance, or cognitive defects. Biochemical assays revealed no obvious differences between the mutant and wildtype alleles in terms of enzymatic activity or mRNA and protein expression levels, suggesting that hexokinase deficiency is not likely to be the underlying mechanism.
Neurodevelopmental Disorder with Visual Defects and Brain Anomalies
In 7 patients from 6 unrelated families with neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA; 618547), Okur et al. (2019) identified 4 different de novo heterozygous missense mutations in the HK1 gene (142600.0006-142600.0009). All mutations occurred at highly conserved residues in the N-terminal regulatory domain. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases, or in an in-house database of over 100,000 exomes. Blood cells from 2 unrelated patients had normal hexokinase activity, suggesting a different pathogenic mechanism. Other functional studies of the variant and studies of patient cells were not performed, but the authors postulated a gain-of-function effect.
Schimke and Grossbard (1968) reviewed studies of hexokinase isozymes.
In a patient with nonspherocytic hemolytic anemia with the so-called HK-Melzo variant of hexokinase deficiency (235700), Bianchi and Magnani (1995) demonstrated compound heterozygosity for mutations in the HK1 gene: a 96-bp deletion of nucleotides 577 to 672 and a 1667T-C transition, resulting in a leu529-to-ser substitution (142600.0002).
For discussion of the leu529-to-ser (L529S) mutation in the HK1 gene that was found in compound heterozygous state in a patient with nonspherocytic hemolytic anemia due to hexokinase deficiency (235700) by Bianchi and Magnani (1995), see 142600.0001.
In all 34 individuals with the Russe type of hereditary motor and sensory neuropathy (HMSNR; 605285) who were studied, Hantke et al. (2009) identified 2 homozygous sequence changes in the HK1 gene, which maps within the candidate disease interval on chromosome 10q. One was a G-to-C transversion at a highly conserved nucleotide in the putative AltT2 exon located in the 5-prime region upstream of HK1 (-3818-195G-C, NM_033497; Chandler, 2013), and the other was an intronic G-to-A transition downstream of the AltT2 change; the G-to-A transition was not highly conserved, and thus not thought to be pathogenic. These 2 variants were found in heterozygous state in 5 of 790 control individuals representing a cross-section of the Gypsy population, but not in 233 Bulgarian controls. AltT2-containing transcripts in the mouse peripheral nerve were rare compared to the coding region of HK1. However, 6 of 8 testis AltT2-containing isoforms were found, with expression patterns differing between the peripheral nerve and the brain and between newborn and adult tissues in mice. There was no difference in HK1 mRNA in Schwann cells derived from patients or controls, and patient cells showed no evidence of HK1 enzyme activity compared to controls. Bioinformatic tools did not suggest an effect of the G-C change on HK1 gene splicing or binding sites for interacting proteins. However, there was evidence that the G-C change may cause a ter-to-tyr substitution in 1 upstream open reading frame that had a non-AUG start codon, which could potentially disrupt HK1 translation regulation. Hantke et al. (2009) speculated that non-OMM-binding HK1 may play a role in the pathogenesis of HMSNR.
Sevilla et al. (2013) found that 11 patients from 9 Roma Gypsy families with progressive hereditary motor and sensory neuropathy were homozygous for the HK1 variant (g.9712G-C) identified by Hantke et al. (2009), and haplotype analysis confirmed a founder effect in this population. The founding ancestor was estimated to have lived at the end of the 18th century, when a population split occurred from a tribal group and the Gypsy population in Spain increased under the rule of Charles III.
In a girl, born of consanguineous parents, with severe nonspherocytic hemolytic anemia due to hexokinase deficiency (235700), who was previously reported by Rijksen et al. (1983), van Wijk et al. (2003) identified a homozygous c.2039C-G transversion in exon 15 of the HK1 gene, resulting in a thr680-to-ser (T680S) substitution at a highly conserved residue in the active site. The mutation, which segregated with the disorder in the family and was not found in 50 controls, was designated 'Utrecht.' In vitro studies of the mutant enzyme showed that it had a 2-fold decrease in affinity for Mg-ATP2 and a markedly decreased affinity for the inhibitor glucose-1,6-diphosphate.
In affected individuals from 5 families (UTAD003, UTAD936, UTAD952, MOGL1, and MOGL2) segregating autosomal dominant retinitis pigmentosa (RP79; 617460), Sullivan et al. (2014) identified heterozygosity for a c.2539G-A transition (c.2539G-A, NM_000188.2) in the HK1 gene, resulting in a glu847-to-lys (E847K) substitution at a highly conserved residue outside of known functional domains. The mutation segregated fully with disease in all families and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Haplotype analysis in the 5 families, 3 of which were from the Acadian population in Louisiana, 1 French Canadian, and 1 Sicilian, demonstrated a shared 450-kb region on chromosome 10, suggesting a founder mutation. One patient in family UTAD003, who was homozygous for the mutation, was diagnosed at age 4 years due to profound nyctalopia; examination at age 33 showed visual acuity reduced to counting fingers in the right eye and 20/200 in the left eye, and he exhibited the classic features of RP on funduscopy, with severe retinal vascular attenuation, diffuse optic disc pallor, extensive and broadly distributed pigment epithelial atrophy with bone spicule accumulation throughout the fundus, and macular atrophy in both eyes.
In affected individuals from a large 4-generation family of European ancestry with RP, Wang et al. (2014) identified heterozygosity for the E847K mutation in the HK1 gene, which segregated with disease in the family with 85% penetrance and was not found in 11,000 in-house exomes. Two asymptomatic family members who also carried the mutation exhibited unaffected vision and no bone-spicule pigmentation at ages 37 and 78 years, respectively. Affected individuals showed no signs of anemia, exercise intolerance, or cognitive defects. Functional analysis in HEK293T cells showed that mutant hexokinase activity as well as mRNA and protein levels were similar to those of the wildtype protein.
In a 34-year-old woman (patient 1) with neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA; 618547), Okur et al. (2019) identified a de novo heterozygous c.1241G-A transition (c.1241G-A, NM_000188.2) in the HK1 gene, resulting in a gly414-to-glu (G414E) substitution at a highly conserved residue in the N-terminal regulatory domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases, or in an in-house database of over 100,000 exomes. Functional studies of the variant and studies of patient cells were not performed.
In a 9-year-old girl (patient 2) with neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA; 618547), Okur et al. (2019) identified a de novo heterozygous c.1252A-G transition (c.1252A-G, NM_000188.2) in the HK1 gene, resulting in a lys418-to-glu (K418E) substitution at a highly conserved residue in the N-terminal regulatory domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases, or in an in-house database of over 100,000 exomes. Hexokinase activity in patient red cells was normal, suggesting a different pathogenic mechanism. Additional functional studies of the variant were not performed.
In 2 unrelated patients (patients 3 and 4) with neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA; 618547), Okur et al. (2019) identified a de novo heterozygous c.1334C-T transition (c.1334C-T, NM_000188.2) in the HK1 gene, resulting in a ser445-to-leu (S445L) substitution at a highly conserved residue in the N-terminal regulatory domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases, or in an in-house database of over 100,000 exomes. Hexokinase activity in patient red cells derived from 1 of the patients was normal, suggesting a different pathogenic mechanism. Additional functional studies of the variant were not performed.
In an 8-year-old boy (patient 5) and 2 sibs who died at 1 year of age (patients 6 and 7), with neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA; 618547), Okur et al. (2019) identified a de novo heterozygous c.1370C-T transition (c.1370C-T, NM000188.2) in the HK1 gene, resulting in a thr457-to-met (T457M) substitution at a highly conserved residue in the N-terminal regulatory domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases, or in an in-house database of over 100,000 exomes. The mutation occurred de novo in patient 5; paternal mosaicism in the blood was excluded in the sibs. Functional studies of the variant and studies of patient cells were not performed.
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