Alternative titles; symbols
HGNC Approved Gene Symbol: H6PD
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38): 1:9,234,774-9,271,337 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.22 | Cortisone reductase deficiency 1 | 604931 | Autosomal recessive | 3 |
Glucose dehydrogenase (GDH), or hexose-6-phosphate dehydrogenase (H6PD; EC 1.1.1.47), is a microsomal enzyme with a dimeric structure that oxidizes glucose-6-phosphate, glucose, galactose-6-phosphate, and 2-deoxyglucose-6-phosphate using NAD or NADP as coenzymes (summary by Krczal et al., 1993).
Mason et al. (1999) isolated and sequenced a cDNA encoding human H6PD. The deduced protein contains 791 amino acids and shares extensive homology with cytosolic G6PD (305900). H6PD is present in most tissues, predominantly in liver, but is not present in red cells (Beutler and Morrison, 1967; Mason et al., 1999).
Mason et al. (1999) determined that the H6PD gene spans 37 kb and contains 5 exons, the fifth of which codes for more than half of the 89-kD protein.
Hameister et al. (1978) showed by somatic cell hybridization that GDH is on chromosome 1. The locus is closely linked (theta less than 0.05) to PGD (172200). King (1982) concluded that GDH is near the end of 1p. The PGD:Rh distance is about 17 cM in the male and 27 cM in the female; thus, GDH may be about 12 cM distal to PGD in the male and 19 cM distal in the female. Carritt et al. (1982) presented evidence that GDH and ENO1 (172430) are distal to PGD and that all 3 loci are distal to 1p36.13. They presented an updated map of 1p, revising that provided by HGM6, the Oslo workshop.
By sequence similarity to a human genomic sequence that had been mapped to chromosome 1p36, Mason et al. (1999) mapped the human H6PD gene to that region.
H6PD is able to catalyze the first 2 reactions of an endolumenal pentose phosphate pathway, thereby generating reduced nicotinamide adenine dinucleotide phosphate (NADPH) within the endoplasmic reticulum. It is distinct from the cytosolic enzyme G6PD (305900), using a separate pool of NAD(P)+ and capable of oxidizing several phosphorylated hexoses (summary by Hewitt et al., 2005).
Cortisone Reductase Deficiency 1
In cortisone reductase deficiency (604931), activation of cortisone to cortisol does not occur, suggesting a defect in 11-beta-hydroxysteroid dehydrogenase type 1 (HSD11B1; 600713), a primary regulator of tissue-specific glucocorticoid bioavailability. In vivo, 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-HSD1) catalyzes the reduction of cortisone to cortisol, whereas purified enzyme acts as a dehydrogenase, converting cortisol to cortisone. Oxoreductase activity can be regained via a NADPH-regeneration system involving the cytosolic enzyme glucose-6-phosphate dehydrogenase (G6PD; 305900); however, because the catalytic domain of 11-beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER), Draper et al. (2003) hypothesized that the endolumenal hexose-6-phosphate dehydrogenase (H6PD) regenerates NADPH in the ER, thereby influencing directionality of 11-beta-HSD1 activity. In 3 individuals with cortisone reductase deficiency, Draper et al. (2003) identified intronic mutations in the HSD11B1 gene (see 600713.0001) in combination with mutations in H6PD (138090.0001, 138090.0002) and proposed a triallelic digenic model of inheritance.
Noting that large-scale population-based studies from 3 centers (Draper et al., 2006; Smit et al., 2007; White, 2005) had shown that the variants found by Draper et al. (2003) were polymorphisms rather than disease-causing mutations, Lavery et al. (2008) restudied 4 patients with cortisone reductase deficiency, including the 3 patients studied by Draper et al. (2003). Lavery et al. (2008) found no mutations or sequence variants in the HSD11B1 gene. Sequencing of the H6PD gene revealed 4 novel and 1 previously reported mutation in homozygous or compound heterozygous state (138090.0003-138090.0006 and 138090.0001, respectively) in all 4 patients. Expression and activity assays demonstrated loss of function for all 5 mutations, which were not found in 120 control chromosomes. Lavery et al. (2008) concluded that cortisone reductase deficiency can be explained solely by inactivation of the H6PD gene and stated that in the earlier study by Draper et al. (2003), these mutations in H6PD were either missed or presumed to be silent and thus of no relevance.
Polymorphism
By the zymogram technique, Tan and Ashton (1976) found 3 phenotypes of G6PD of the H type in human saliva. Family and population studies suggested that these phenotypes are the products of an autosomal locus with 2 alleles, Sgd-1 and Sgd-2. In addition to oxidizing other hexose-6-phosphates, H6PD uses NAD as well as NADP as a coenzyme. It is present in the microsomes. The existence of a separate G6PD isozyme in fetal brain was suggested by Toncheva et al. (1982), who thought it was probably determined by an autosomal gene.
King and Cook (1981) found polymorphism by isoelectric focusing. The frequency of 3 alleles was found to be 0.723, 0.194, and 0.083. Krczal et al. (1993) calculated the frequencies of the 3 alleles in southwestern Germany to be 0.70, 0.18, and 0.12. Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Multiple Sclerosis 4
For discussion of a possible association between variation in the H6PD gene and multiple sclerosis, see MS4 (612596).
H6pd-null mice are relatively insensitive to glucocorticoids, exhibiting fasting hypoglycemia, increased insulin sensitivity despite elevated circulating corticosterone, and increased basal and insulin-stimulated glucose uptake in muscle normally enriched in type II (fast) fibers, which have increased glycogen content. Lavery et al. (2008) found H6pd-null mice developed severe skeletal myopathy characterized by switching of type II to type I (slow) fibers. Affected muscles had normal sarcomeric structure but contained large intrafibrillar membranous vacuoles, abnormal sarcoplasmic reticulum (SR) structure, and dysregulated expression of SR proteins involved in calcium metabolism. There was also overexpression of genes involved in the unfolded protein response pathway. Lavery et al. (2008) concluded that the absence of H6PD induces myopathy by altering the SR redox state, thereby impairing protein folding and activating the unfolded protein response pathway.
In the Scottish female with apparent cortisone reductase deficiency (CORTRD1; 604931) reported by Jamieson et al. (1999), Draper et al. (2003) detected a heterozygous 29-bp insertion between nucleotides 620 and 621 of the H6PD gene. Functional studies in hepatic WRL68 cells demonstrated that the 620ins29bp mutant was devoid of H6PDH activity. The 620_621ins29 mutation was found in none of 100 Scottish controls. In this patient, Draper et al. (2003) also detected homozygosity for a pair of linked intronic mutations in the HSD11B1 gene (600713.0001). In 100 Scottish controls homozygosity for these intronic changes had a frequency of 2%. The patient reported by Jamieson et al. (1999) presented at the age of 36 years with hirsutism, oligomenorrhea, obesity, acne, and infertility, features resembling those of polycystic ovary syndrome (PCOS; 184700).
In the Scottish woman with cortisone reductase deficiency reported by Jamieson et al. (1999), Lavery et al. (2008) detected compound heterozygosity for the 620_621ins29 mutation in H6PD and a 960G-A transition in exon 4 (138090.0003). The 29-bp insertion caused a frameshift predicted to result in an in-frame stop codon that truncates the protein by 268 amino acids (Asp620fsTer3). No mutations or sequence variants were detected in the HSD11B1 gene.
This variant, formerly titled CORTISONE REDUCTASE DEFICIENCY, has been reclassified based on the findings of White (2005), Draper et al. (2006), Smit et al. (2007), and Lavery et al. (2008).
In 2 subjects with cortisone reductase deficiency (see 604931), Draper et al. (2003) found heterozygosity for a double intronic mutation in HSD11B1 (600713.0001) and homozygosity for an arg453-to-gln (R453Q) mutation in H6PD. One of the subjects was an Indo-Asian female who presented with longstanding hirsutism at 44 years of age. The other was a 6-year-old male of Polish descent, who presented with gonadotropin-independent precocious puberty and hyperandrogenism.
Because the phenotype of cortisone reductase deficiency resembles that of polycystic ovary syndrome (PCOS; see 184700), San Millan et al. (2005) investigated the R453Q variant of H6PD and the 83557insA variant of HSD11B1 (see 600713.0001) in 116 patients with PCOS and 76 nonhyperandrogenic controls. Four controls and 5 patients presented 3 of 4 mutant alleles in H6PD R453Q and HSD11B1 83557insA, which is the genotype observed in some subjects with cortisone reductase deficiency. Estimates of 11-beta-HSD oxoreductase activity were measured in 6 of these 9 women, ruling out cortisone reductase deficiency. Patients homozygous for the R453 allele, which was more frequent in PCOS patients, presented with increased cortisol and 17-hydroxyprogesterone levels compared with carriers of Q453 alleles; these differences were not observed in controls. HSD11B1 83557insA genotypes were not associated with PCOS and did not influence any phenotypic variable. San Millan et al. (2005) concluded that digenic triallelic genotypes of the H6PD R453Q variant and HSD11B1 83557insA mutation do not always cause CRD. They also suggested that the H6PD R453Q variant is associated with PCOS and might influence its phenotype by influencing adrenal activity.
In a population-based association study, White (2005) genotyped 3,551 individuals for the 83597T-G polymorphism in intron 3 of the HSD11B1 gene (see 600713.0001) and the R453Q polymorphism in the H6PD gene. Both polymorphisms occurred more frequently than had been reported, with the so-called 'apparent CRD (ACRD) genotypes' (at least 3 of 4 minor alleles present) occurring in 7% of subjects. There were no associations between genotype and body mass index; waist/hip ratio; visceral adiposity; measures of insulin sensitivity; levels of testosterone, FSH, or LH (in females); or risk of PCOS. In addition, there was no genotype effect on urinary free cortisol/cortisone or corticosteroid metabolite ratios, which were measured in 10 subjects, each carrying 0, 3, or 4 minor alleles. White (2005) concluded that previously reported associations of ACRD with HSD11B1 and H6PD alleles represented ascertainment bias, but noted that rare severe mutations in these genes could not be ruled out.
In a case-control study involving 256 nuclear families ascertained from PCOS offspring, 213 singleton cases, and 549 controls, Draper et al. (2006) analyzed CRD-related variants in the HSD11B1 (83597T-G; rs12086634) and H6PD (R453Q; rs6688832) genes but found no differences in genotype distribution between PCOS cases and controls. Draper et al. (2006) concluded that the variants do not influence susceptibility to PCOS.
Smit et al. (2007) analyzed the 83557insA polymorphism in the HSD11B1 gene and the R453Q polymorphism in H6PD in 6,452 elderly Caucasian individuals from 2 population-based cohorts and found no association between genotype distribution or combined genotypes on body mass index, adrenal androgen production, waist-to-hip ratio, systolic and diastolic blood pressure, fasting glucose levels, glucose tolerance test, or incidence of dementia (see 600274). Given the high frequency of the 2 polymorphisms in these 2 Caucasian populations, with 3.8% and 4.0% carrying at least 3 affected alleles, respectively, Smit et al. (2007) concluded that it was very unlikely that these SNPs interact to cause CRD.
Lavery et al. (2008) could not demonstrate an effect of the R453Q variant on enzyme activity, in contrast to the findings of Draper et al. (2003), and noted that reasons for the discrepancy remained to be fully elucidated.
In the Scottish woman with cortisone reductase deficiency (CORTRD1; 604931) originally reported by Jamieson et al. (1999), Lavery et al. (2008) identified compound heterozygosity for a 620_621ins29 mutation in exon 5 of the H6PD gene (138090.0001) and a 960G-A transition in exon 4. The latter mutation generates a strong donor splice site consensus sequence, and RT-PCR performed on the patient's cDNA indicated that the activated donor splice site was used, resulting in a 54-nucleotide truncated mRNA, with loss of 18 amino acids. An additional mRNA product retaining intron 4 was also observed, implying variant mutant splicing. Neither mutation was found in 120 control chromosomes, and functional analysis in HEK293 cells demonstrated total loss of function with both the 29-bp insertion and the 960G-A mutation.
In an Indo-Asian woman with cortisone reductase deficiency (CORTRD1; 604931), previously studied by Draper et al. (2003), Lavery et al. (2008) identified homozygosity for a 1076G-A transition in exon 5 of the H6PD gene, resulting in a gly359-to-asp (G359D) substitution at a highly conserved residue. The mutation was not found in 120 control chromosomes, and functional analysis of this mutation in HEK293 cells demonstrated total loss of function. No mutations or sequence variants were detected in the HSD11B1 gene (600713).
In a boy of Polish descent with cortisone reductase deficiency (CORTRD1; 604931), previously studied by Draper et al. (2003), Lavery et al. (2008) identified homozygosity for a 948C-G transversion in exon 4 of the H6PD gene, resulting in a tyr316-to-ter (Y316X) substitution, predicted to truncate the protein by 575 amino acids. The mutation was not found in 120 control chromosomes, and functional analysis of the mutation in HEK293 cells demonstrated total loss of function. No mutations or sequence variants were detected in the HSD11B1 gene (600713).
In a woman with cortisone reductase deficiency (CORTRD1; 604931), originally reported by Biason-Lauber et al. (2000), Lavery et al. (2008) identified homozygosity for a 1-bp deletion (325delC) in exon 2 of the H6PD gene, causing a frameshift resulting in a premature stop codon (Arg109AlafsTer3). The mutation was not found in 120 control chromosomes, and functional analysis of the 325delC mutant in HEK293 cells demonstrated total loss of function.
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