Alternative titles; symbols
HGNC Approved Gene Symbol: GALE
SNOMEDCT: 8849004;
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:23,795,599-23,800,754 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.11 | Galactose epimerase deficiency | 230350 | Autosomal recessive | 3 |
| Thrombocytopenia 13, syndromic | 620776 | 3 |
The GALE gene encodes UDP-galactose-4-prime-epimerase (EC 5.1.3.2), which catalyzes the interconversion of UDP-galactose and UDP-glucose, important for galactose metabolism, and the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine, important for protein glycosylation (Piller et al., 1983; summary by Seo et al., 2019 and Marin-Quilez et al., 2023).
Daude et al. (1995) reported the cloning, characterization, and mapping of a full-length cDNA encoding human GALE. The cDNA encodes a predicted protein of 348 amino acids with a molecular mass of 38,266 Da. The human enzyme is similar to that of rat (87% identity), Kluyveromyces lactis (53%), and E. coli (51%); this similarity allowed Daude et al. (1995) to build a homology model based on the bacterial crystal structure.
Marin-Quilez et al. (2023) found that GALE is poorly expressed in CD34+ hematopoietic progenitor cells, but is increased during megakaryocyte differentiation. GALE expression was reduced in released platelet-like particles. GALE localized to the endoplasmic reticulum in megakaryocytes.
The galactose epimerase enzyme catalyzes 2 distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. This has been shown by purification of the bifunctional enzyme (Piller et al., 1983) and by simultaneous loss of both activities in a Chinese hamster ovary cell line (Kingsley et al., 1986).
Maceratesi et al. (1998) characterized the entire coding sequence of the GALE gene, which contains 11 exons.
By study of human-mouse somatic cell hybrids, Lin et al. (1978) showed that the gene encoding uridine diphosphate galactose-4-epimerase is on chromosome 1. Lin et al. (1979) narrowed the assignment to 1pter-p32.
Stumpf (2024) mapped the GALE gene to chromosome 1p36.11 based on an alignment of the GALE sequence (GenBank BC001273) with the genomic sequence (GRCh38).
Galactosemia III
In a patient with galactosemia III (GALAC3; 230350), or galactose epimerase deficiency, Alano et al. (1998) identified compound heterozygous mutations in the GALE gene (N34S, 606953.0002; L183P, 606953.0001). The same patient was reported by Quimby et al. (1997).
Maceratesi et al. (1998) screened for mutations in galactose epimerase-deficient individuals and identified 5 mutations in the GALE gene. The patients were either homozygous or compound heterozygous for the mutations.
Syndromic Thrombocytopenia 13
In 6 patients from a consanguineous Bedouin family (AH) with syndromic thrombocytopenia-13 (THC13; 620776), Seo et al. (2019) identified a homozygous missense mutation in the GALE gene (R51W; 606953.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed. In vitro functional expression studies showed that the R51W protein had about 40% residual activity for both interconversion functions compared to wildtype and showed reduced NAD+ binding (41% reduction compared to wildtype). The melting point of the R51W mutant was lower than controls, indicating thermal instability. Knockdown of GALE in CD34+ hematopoietic progenitor cells slowed the proliferation of megakaryocyte precursors, and the colonies that formed were larger than controls. These findings suggested that loss of GALE results in defective megakaryocyte differentiation. The authors postulated that deficiency of glycosylation resulting from decreased levels of GALE due to thermal instability may have a detrimental effect on hematopoiesis.
In a 2-year-old Hispanic boy with THC13, Febres-Aldana et al. (2020) identified compound heterozygous missense mutations in the GALE gene: R51W and G237D (606953.0010). The mutations, which were found by whole-genome sequencing, were each inherited from an unaffected parent. Both mutations were present at low frequencies in the heterozygous state in gnomAD.
In a 19-year-old Hispanic woman with THC13, Markovitz et al. (2021) identified a homozygous T150M mutation in the GALE gene (606953.0011). The mutation was found by whole-exome sequencing. The patient had reduced hemolysate and lymphocyte GALE activity with respect to UDP-Gal, but normal lymphocyte GALE activity with respect to UDP-GalNAc.
In 3 patients from 2 unrelated families with THC13, Marin-Quilez et al. (2023) identified compound heterozygous mutations in the GALE gene (606953.0011-606953.0014). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. All mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets. Patient peripheral blood progenitor cells showed normal megakaryocyte differentiation, although there was a 60 to 80% reduction in GALE expression in mature megakaryocytes and impaired formation of proplatelets with abnormal morphology and altered distribution of actin (see 102630) and filamin A (300017). Analysis of patient platelets showed decreased GALE levels and enzymatic activity, decreased glycosylation patterns, and increased apoptosis compared to controls. Patient platelets had reduced aggregation in response to stimulation associated with a sharp reduction in glycosylation and membrane expression of GP1BA (606672) and ITGB1 (135630), which were retained abnormally in the endoplasmic reticulum. VWF (613160) expression was also decreased on patient megakaryocytes compared to controls. ITGA2B (607759)/ITGB3 (173470) expression and function were preserved, as was the thrombopoietin (600044) receptor (MPL; 159530).
Wohlers et al. (1999) reported a V94M (606953.0008) missense mutation in both GALE alleles of a patient with the generalized form of galactose epimerase deficiency. The same mutation was found in homozygous state in 2 other patients with the same clinical picture. The specific activity of the mutant protein expressed in yeast was severely reduced with regard to UDP-galactose and partially reduced with regard to UDP-N-actetylgalactosamine. In contrast, 2 GALE-variant proteins associated with peripheral galactose epimerase deficiency, L313M (606953.0006) and D103G (606953.0004), demonstrated near-normal levels of activity with regard to both substrates, but a third allele, G90E (606953.0003), demonstrated little if any detectable activity, despite near-normal abundance. Thermal lability and protease sensitivity studies demonstrated compromised stability in all of the partially active mutant enzymes. Two clinically relevant questions remained unanswered after this study: first, whether epimerase-deficiency galactosemia is clinically a binary disorder or a continuum, and second, whether a genotype-phenotype pattern is emerging.
Yeast Studies
To enable structural and functional studies of both wildtype and patient-derived alleles of the GALE gene, Quimby et al. (1997) developed and applied a null-background yeast expression system for analysis of the human enzyme. They demonstrated that human wildtype GALE sequences phenotypically complemented a yeast gal10 deletion, and they characterized the wildtype human enzyme isolated from these cells. Furthermore, they expressed and characterized 2 mutant alleles, leu183 to pro (L183P; 606953.0001) and asn34 to ser (N34S; 606953.0002), derived from a patient with no detectable GALE activity in red blood cells but with approximately 14% activity in cultured lymphoblasts. Analyses of crude extracts of yeast expressing the L183P mutant form of human GALE demonstrated 4% wildtype activity and 6% wildtype abundance. Extracts of yeast expressing the other human mutation, N34S, demonstrated approximately 70% wildtype activity and normal abundance. However, yeast coexpressing both mutations exhibited only approximately 7% wildtype levels of activity, thereby confirming the functional impact of both substitutions and suggesting that dominant-negative interaction may exist between the mutant alleles found in this patient.
Quimby et al. (1997) identified compound heterozygosity for a leu183-to-pro (L183P) and an asn34-to-ser (N34S; 606953.0002) mutation in the GALE gene in a 5-year-old male with galactose epimerase deficiency (GALAC3; 230350) born to a Caucasian mother and a Pakistani father. Newborn screening at 6 and 9 days of age showed abnormally elevated galactose sugars but normal GALT (606999) activity. The child remained clinically well on a lactose-containing diet, with no hepatomegaly, liver disease, vomiting, or acidosis. At approximately 1 year of age he began experiencing delays in gross motor development, and at age 5 years he exhibited mild to moderate mental retardation with global delays in language and cognitive abilities, although he was otherwise healthy.
For discussion of the asn34-to-ser (N34S) mutation in the GALE gene that was found in compound heterozygous state in a patient with galactose epimerase deficiency (230350) by Quimby et al. (1997), see 606953.0001.
In an Asian patient with galactose epimerase deficiency (GALAC3; 230350), Maceratesi et al. (1998) identified on 1 GALE allele a GGG-to-GAG transition that changed codon 90 from glycine to glutamic acid (G90E). The other allele was not characterized.
On both alleles of the GALE gene in an Asian patient with galactose epimerase deficiency (GALAC3; 230350), Maceratesi et al. (1998) found a GAT-to-GGT transition in the GALE gene that changed an aspartic acid at codon 103 to glycine (D103G).
In an African American patient with galactose epimerase deficiency (GALAC3; 230350), Maceratesi et al. (1998) identified a homozygous AAG-to-AGG transition in the GALE gene that changed codon 257 from lysine to arginine (K257R).
In an Asian patient with galactose epimerase deficiency (GALAC3; 230350), Maceratesi et al. (1998) found a CTG-to-ATG transversion in the GALE gene that changed codon 313 from leucine to methionine (L313M). The patient was heterozygous for this mutation. The other mutation was not identified.
Maceratesi et al. (1998) found that 1 African American patient with galactose epimerase deficiency (GALAC3; 230350) was heterozygous for a GGG-to-GAG transition in the GALE gene that changed codon 319 from glycine to glutamic acid (G319E). The other mutation was not identified.
In what they claimed to be the first case of molecularly characterized severe galactose epimerase deficiency (GALAC3; 230350), Wohlers et al. (1999) identified a homozygous val94-to-met (V94M) missense mutation in the GALE gene. The patient was the product of a consanguineous marriage and had been described by Holton et al. (1981) and Henderson et al. (1983). She presented at age 5 days with symptoms of classic galactosemia (230400), including vomiting, hypotonia, jaundice, galactosuria, and hepatomegaly. Enzyme activities of galactose-1 phosphate uridylyltransferase (606999) and galactokinase (604313) were within normal limits. GALE activity, however, was deficient both in erythrocytes and in cultured skin fibroblasts. At age 19 months, the child remained hypotonic, with an enlarged spleen and developmental delay, despite a galactose-restricted diet (Henderson et al., 1983). Later in life, she was noted to have nerve deafness and moderate learning difficulties, but there was no evidence of ovarian dysfunction.
The V94M protein is impaired relative to the wildtype enzyme predominantly at the level of V(max) rather than K(m). To address the molecular consequences of the mutation on the 3-dimensional architecture of the enzyme, Thoden et al. (2001) solved the structures of the V94M-substituted human epimerase complexed with NADH and UDP-glucose, UDP-galactose, UDP-GlcNAc, or UDP-GalNAc. They found that the net effect of the V94M substitution is an opening up of the ala93-to-glu96 surface loop, which allows free rotation of the sugars into nonproductive binding modes.
In 6 patients from a consanguineous Bedouin family (AH) with syndromic thrombocytopenia-13 (THC13; 620776), Seo et al. (2019) identified a homozygous c.151C-T transition (c.151C-T, NM_001127621) in the GALE gene, resulting in an arg51-to-trp (R51W) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient cells were not performed. In vitro functional expression studies showed that the R51W protein had about 40% residual activity for both interconversion functions compared to wildtype and showed reduced NAD+ binding (41% reduction compared to wildtype). Of note, the mutant protein was able to rescue yeast growth upon galactose challenge in gal10-null yeast (gal10 is the homologous gene to GALE and catalyzes the interconversion of UDP-galactose and UDP-glucose, but not the interconversion of UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine). Accordingly, the patients did not have clinical signs of galactosemia. The melting point of the R51W mutant was lower than controls, indicating thermal instability. The authors postulated that deficiency of glycosylation resulting from decreased levels of GALE due to thermal instability may have a detrimental effect on normal glycosylation and hematopoiesis.
For discussion of the R51W mutation in the GALE gene that was found in compound heterozygous state in a 2-year-old Hispanic boy with THC13 by Febres-Aldana et al. (2020), see 606953.0010.
In a 2-year-old Hispanic boy with syndromic thrombocytopenia-13 (THC13; 620776), Febres-Aldana et al. (2020) identified compound heterozygous missense mutations in the GALE gene: a c.710G-A transition, resulting in a gly237-to-asp (G237D) substitution at a conserved residue, and R51W (606953.0009). The mutations, which were found by whole-genome sequencing, were each inherited from an unaffected parent. Both mutations were present at low frequencies in the heterozygous state in gnomAD. GALE activity in patient red blood cells was decreased compared to controls. The patient had pancytopenia, mitral and tricuspid valve malformations, and pyloric stenosis, but did not have signs of classic galactosemia. The authors postulated that GALE activity in this patient was sufficient to prevent toxic accumulation of galactose, but may be insufficient to compensate for increased demand of UDP-glcNAc/USP-galNAc substrates in cells with higher demand for these glycosylation precursors. Since normal hematopoiesis and genes involved in atrioventricular valve morphogenesis require proper N-glycosylation for adequate functionality, a deficit in N-glycosylation could explain the patient's phenotype.
In a 19-year-old Hispanic woman, born of consanguineous parents, with syndromic thrombocytopenia-13 (THC13; 620776), Markovitz et al. (2021) identified a homozygous c.449C-T transition (c.449C-T, NM_000403.3) in exon 5 in the GALE gene, resulting in a thr150-to-met (T150M) substitution. The mutation was found by whole-exome sequencing. The patient had reduced hemolysate and lymphocyte GALE activity with respect to UDP-Gal, but normal lymphocyte GALE activity with respect to UDP-GalNAc.
In 2 adult sibs (family A) with THC13, Marin-Quilez et al. (2023) identified compound heterozygous mutations in the GALE gene: T150M and a 4-bp insertion (c.230_231insTGTT; 606953.0012) in exon 3, predicted to result in a frameshift and premature termination (Lys78ValfsTer32). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets.
For discussion of the 4-bp insertion (c.230_231insTGTT, NM_001127621.2) in exon 3 of the GALE gene, predicted to result in a frameshift and premature termination (Lys78ValfsTer32), that was found in compound heterozygous state in 2 sibs (family A) with syndromic thrombocytopenia-13 (THC13; 620776) by Marin-Quilez et al. (2023), see 606953.0011.
In a 38-year-old man (family B) with syndromic thrombocytopenia-13 (THC13; 620776), Marin-Quilez et al. (2023) identified compound heterozygous mutations in the GALE gene: a c.382G-A transition (c.382G-A, NM_001127621.2), resulting in a val128-to-met (V128M) substitution, and a c.668T-C transition in exon 7, resulting in a leu223-to-pro substitution (L223P; 606953.0014). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations occurred near the NAD+ binding site and resulted in significantly impaired GALE activity in patient platelets.
For discussion of the c.668T-C transition (c.668T-C, NM_001127621.2) in exon 7 of the GALE gene, resulting in a leu223-to-pro (L223P) substitution that was found in compound heterozygous state in a patient with syndromic thrombocytopenia-13 (THC13; 620776) by Marin-Quilez et al. (2023), see 606953.0013.
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