GALE
protein-codingUDP-galactose-4-epimerase, the group of Short chain dehydrogenase/reductase superfamily
Gene summary
This gene encodes UDP-galactose-4-epimerase which catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine as a necessary precursor for the synthesis of glycoproteins and glycolipids. Mutations in this gene result in epimerase-deficiency galactosemia, also referred to as galactosemia type 3, a disease characterized by liver damage, early-onset cataracts, deafness and cognitive disability, with symptoms ranging from mild ('peripheral' form) to severe ('generalized' form). Multiple alternatively spliced transcripts encoding the same protein have been identified. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009257
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009257
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009257
Submitter: ClinGen
*GALE* was first reported in relation to autosomal recessive galactose epimerase deficiency in 1997 (Quimby et al., PMID:9326324). Galactose epimerase deficiency is described in the literature as a spectrum with general, peripheral, and intermediate forms. The general form of the disease is associated with markedly decreased enzyme activity in all tissues in addition to hypotonia, jaundice, hepatomegaly, and developmental delays. Immediate dietary intervention by putting patients on a galactose/lactose-free diet can help prevent further development of these symptoms. The peripheral form is accompanied by enzyme activity deficient in blood cells and normal in other tissues. The intermediate form is similarly demonstrated by deficiency in blood cells, yet can have up to 50% enzyme activity in other tissues (GeneReviews, PMID: 20301295). Recently, thrombocytopenia has been reported as an additional feature of this disease in multiple affected families, and has been recognized as part of the expanded phenotype of galactose epimerase deficiency (PMIDs:7562286, 36395340). 19 variants (17 missense, 2 frameshift) that have been reported in 15 probands in 6 publications (PMIDs: 36395340, 34159722, 30247636, 36056436, 16301867, 9326324) are included in this curation. Recurrent variant V94M is associated with an especially severe phenotype (PMIDs:36056436, 28247339, 9973283). One consanguineous family with a history of thrombocytopenia was reported in association with the *GALE* variant c.151C>T (p.Arg51Trp). The variant segregated with the disease in 5 affected and 10 unaffected individuals (Estimated LOD score: 4.26, PMID:30247636). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached (if applicable. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by biochemical assays, functional alteration experiments, model systems, and rescue evidence (PMIDs: 28877911, 20519568, 3948246, 29409891, 7305435). First, *GALE* is known to encode the galactose epimerase enzyme. A deficiency in this enzyme would lead to excess of galactose products according to the Leloir pathway, which is consistent with hypergalactosemia observed in patients with *GALE* deficiency (PMID:7305435). Next, *GALT* is a gene that encodes a separate protein within the Leloir pathway, and is classified as definitely associated with hereditary galactosemia by the General Inborn Errors of Metabolism GCEP (PMID:29409891). Yeast cells with the homolog GAL10 gene removed were functionally altered compared to control cells, as they failed to grow on galactose-based media, which reiterates the importance of this protein in the conversion of galactose to glucose (PMID:3948246). An shRNA knockdown of gale in mice was included as part of this curation, but not scored due to low phenotypic overlap with the disease and absence of gale enzymatic testing (PMID:28877911). An entire cohort (100%) of drosophila with Gale deficiency (and 2 LOF alleles) died within the embryonic stage. Drosophila with partial Gale deficiency (1 LOF allele) survived into adulthood, but could only survive if fed a galactose-free diet. Humans with gale epimerase deficiency can have developmental delays, and can see improvement in symptoms by removing galactose from the diet. When a human copy of *GALE* was inserted into the null Gale drosophila, enzyme activity was restored to wildtype, and survival frequency was also rescued to wild-type levels (PMID:20519568). In summary, *GALE* is definitively associated with autosomal recessive galactose epimerase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism on the meeting date 8/25/2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0009257
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0958333
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009257
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Hematologic; Neurologic; Ophthalmologic; Renal
Intervention: Biochemical; Hematologic; Neurologic
Rationale: The generalized form of Galactosemia III, which typically manifests clinically in infancy upon exposure to lactose-containing diet, can result in lethal sequelae, and can be treated or prevented through dietary means (galactose/lactose restriction); Though data are unclear, individuals with intermediate forms of Galactosemia III may also benefit from galactose restriction as well; Thrombocytopenia, autosomal recessive 13 may involve increased risk of bleeding, and awareness may allow preventative measures as well as management of bleeding episodes; Thrombocytopenia, autosomal recessive 13 may involve cardiovascular anomalies, and awareness may allow early identification and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GALE variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001008216.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 111 | 114 | |||
| missense | 3 | 12 | 107 | 3 | 125 | |
| nonsense | 3 | 5 | 1 | 9 | ||
| start loss | 2 | 1 | 3 | |||
| frameshift | 16 | 8 | 2 | 26 | ||
| splice donor/acceptor (+/-2bp) | 14 | 5 | 19 | |||
| Total | 24 | 40 | 118 | 114 | 0 | 296 |
Highest pathogenic variant AF is 0.00006195887
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001008217.1 | 10 | MANE Select | |
| Ensembl | ENSP00000483375.1 | 10 | MANE Select | |
| RefSeq | NP_000394.2 | 10 | Standard | |
| RefSeq | NP_001121093.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- UDP-<i>N</i>-acetyl-D-galactosamine biosynthesis II
- Galactose metabolism - Homo sapiens (human)
- Amino sugar and nucleotide sugar metabolism - Homo sapiens (human)
- Galactosemia III
- Galactosemia II (GALK)
Biological Process
- galactose catabolic process
- galactose catabolic process via UDP-galactose
Molecular Function
- UDP-N-acetylglucosamine 4-epimerase activity
- UDP-glucose 4-epimerase activity
- identical protein binding
- protein homodimerization activity
Cellular Component
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374497
- Coding exons
- 10
- Length
- 5183
- Individuals with no LoFs
- 125705
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 43
- Defined
- 125748
- p
- 0.000171
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.322 | 217 | 204 | 1.06 | 0.0000133 | 2244 |
| Missense (PolyPhen) | 89 | 97.481 | 0.913 | 1045 | ||
| Synonymous | 0.0148 | 85 | 85.2 | 0.998 | 0.00000562 | 704 |
| Loss of Function | 0.332 | 16 | 17.5 | 0.914 | 8.58e-7 | 213 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00035 | 0.00035 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00049 | 0.00049 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00013 | 0.00013 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes two distinct but analogous reactions: the reversible epimerization of UDP-glucose to UDP-galactose and the reversible epimerization of UDP-N-acetylglucosamine to UDP-N- acetylgalactosamine. The reaction with UDP-Gal plays a critical role in the Leloir pathway of galactose catabolism in which galactose is converted to the glycolytic intermediate glucose 6- phosphate. It contributes to the catabolism of dietary galactose and enables the endogenous biosynthesis of both UDP-Gal and UDP- GalNAc when exogenous sources are limited. Both UDP-sugar interconversions are important in the synthesis of glycoproteins and glycolipids. {ECO:0000269|PubMed:22654673, ECO:0000303|PubMed:23732289}.;
- Disease
- DISEASE: Epimerase-deficiency galactosemia (EDG) [MIM:230350]: Clinical features include early-onset cataracts, liver damage, deafness and mental retardation. There are two clinically distinct forms of EDG. (1) A benign, or 'peripheral' form with no detectable GALE activity in red blood cells and characterized by mild symptoms. Some patients may suffer no symptoms beyond raised levels of galactose-1-phosphate in the blood. (2) A much rarer 'generalized' form with undetectable levels of GALE activity in all tissues and resulting in severe features such as restricted growth and mental development. {ECO:0000269|PubMed:11279193, ECO:0000269|PubMed:11903335, ECO:0000269|PubMed:15639193, ECO:0000269|PubMed:16301867, ECO:0000269|PubMed:16302980, ECO:0000269|PubMed:9326324, ECO:0000269|PubMed:9538513, ECO:0000269|PubMed:9973283}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.569
Intolerance Scores
- LoFtool
- 0.0621
- RVIS EVS
- -0.56
- RVIS percentile EVS
- 19.73
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.467
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |