Alternative titles; symbols
HGNC Approved Gene Symbol: GALM
SNOMEDCT: 1187616008;
Cytogenetic location: 2p22.1 Genomic coordinates (GRCh38): 2:38,666,114-38,734,765 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p22.1 | Galactosemia IV | 618881 | Autosomal recessive | 3 |
The GALM gene encodes the enzyme galactose mutarotase (EC 5.1.3.3), which converts beta-D-galactose to alpha-D-galactose, the first step in the Leloir pathway (summary by Wada et al., 2019).
By database searching with the protein sequence of Lactococcus lactis galactose mutarotase (Galm) as query, Timson and Reece (2003) identified human GALM. Bacterially expressed and purified GALM protein has a molecular mass of 32 kD by analytic gel filtration.
Using polarimetry, Timson and Reece (2003) showed that addition of GALM to sugar solutions of galactose or glucose resulted in an increase in the sugar mutarotation rate, with a higher rate observed for galactose. Timson and Reece (2003) individually mutated 3 GALM residues implicated in catalysis by the crystal structure of L. lactis Galm and found that the mutant GALM proteins had reduced mutarotase activity.
Thoden et al. (2004) determined the x-ray crystallographic structure of GALM, both unbound and complexed with beta-D-galactose. GALM folds into 2 alpha helices and 29 beta strands connected by 25 classical reverse turns. Two cis-peptide bonds are present, and the side chains of glu307 and his176 are in locations appropriate to act as catalytic base and acid, respectively. No significant structural changes were observed upon galactose binding to GALM.
Chu et al. (1975) presented cell-hybrid evidence for synteny of gal-1-PT, acid phosphatase, MDH-1 and gal-plus-activator (GLAT) and for assignment to chromosome 2.
In 8 unrelated Japanese children with galactosemia (GALAC4; 618881) in whom no mutations were identified in the GALK1 (604313), GALE (606953), or GALT (606999) genes, Wada et al. (2019) identified 5 different mutations in homozygous or compound heterozygous state in the GALM gene (137030.0001-137030.0005). Mutations in the first 2 patients were found by trio-based whole-exome sequencing, and mutations in subsequent patients were identified by Sanger sequencing. Segregation of the mutations with the phenotype was confirmed in 4 families. GALM activity was reduced in lymphoblastoid cells from 2 patients, and peripheral blood mononuclear cells from 3 patients lacked GALM protein compared with control cells. Cycloheximide protein stability assays with 3 variants indicated markedly reduced protein stability compared to wildtype. The findings suggested a loss-of-function effect of the mutations.
Iwasawa et al. (2019) examined 66 prevalent, unreported GALM variants in the ExAC database (57 missense, 7 stop-gain, 2 frameshift) by expression studies in COS-7 cells and/or enzyme function studies. Twenty-nine variants produced no or faint protein expression and were classified as pathogenic. Five variants had low protein expression and low enzyme activity and were classified as likely pathogenic. The remaining 32 variants were classified as benign based on normal enzyme activity in 30 and mildly reduced enzyme activity in 2. An additional prevalent splice site mutation was considered to be pathogenic.
In 2 unrelated Japanese children with galactosemia IV (GALAC4; 618881), Wada et al. (2019) identified compound heterozygosity for mutations in the GALM gene. Both children carried a 1-bp deletion (c.294delC, NM_138801.2), resulting in a frameshift and a premature termination codon (Ile99LeufsTer46); patient 1 also carried a c.244C-T transition, resulting in an arg82-to-ter (R82X; 137030.0002) substitution, and patient 2 carried a c.799C-G transversion, resulting in an arg267-to-gly (R267G; 137030.0003) substitution at a conserved residue. The mutations were found by trio-based exome sequencing and confirmed by Sanger sequencing. By Sanger sequencing in 6 additional children with galactosemia, Wada et al. (2019) identified homozygosity for the c.294delC mutation in 1 (patient 3). The mutations segregated with the disorder in all 3 families. Wada et al. (2019) showed absent GALM enzyme activity in lymphoblastoid cells and absent protein expression in PBMCs from the homozygous patient. Expression of GALM with the deletion or R82X variants in 293FT cells showed reduced protein expression, whereas the R267G variant showed reduced protein expression and stability compared to wildtype.
For discussion of the c.244C-T transition (c.244C-T, NM_138801.2) in the GALM gene, resulting in an arg82-to-ter (R82X) substitution, that was found in compound heterozygous state in a patient with galactosemia IV (GALAC4; 618881) by Wada et al. (2019), see 137030.0001.
For discussion of the c.799C-G transition (c.799C-G, NM_138801.2) in the GALM gene, resulting in an arg267-to-gly (R267G) substitution, that was found in compound heterozygous state in patients with galactosemia IV (GALAC4; 618881) by Wada et al. (2019), see 137030.0001 and 137030.0004.
By Sanger sequencing of the GALM gene in 6 unrelated Japanese patients with galactosemia IV (GALAC4; 618881), Wada et al. (2019) identified a c.424G-A transition (c.424G-A, NM_138801.2), resulting in a gly142-to-arg (G142R) substitution at a conserved residue. The mutation was homozygous in 3 patients (patients 5, 6, 8) and compound heterozygous with a c.799C-G transition, resulting in an arg267-to-gly (R267G; 137030.0003) substitution, in 1 (patient 7). Expression of GALM with either of the variants in 293FT cells showed reduced protein expression and stability compared to wildtype. The G142R mutation was found in homozygous state in only 1 individual, in the African population, in the gnomAD database.
By Sanger sequencing of the GALM gene in a Japanese child (patient 4) with galactosemia IV (GALAC4; 618881), Wada et al. (2019) identified homozygosity for a c.932G-A transition (c.932G-A, NM_138801.2), resulting in a trp311-to-ter (W311X) substitution. Expression of GALM with the W311X variant in 293FT cells showed reduced protein expression and stability compared to wildtype.
Chu, E. H. Y., Chang, C. C., Sun, N. C. Synteny of the human genes for gal-1-PT, ACP-1, MDH-1, and GAL+-ACT and assignment to chromosome 2. Birth Defects Orig. Art. Ser. 11(3): 103-106, 1975. Note: Alternate: Cytogenet. Cell Genet. 14: 273-276, 1975. [PubMed: 1203465]
Iwasawa, S., Kikuchi, A., Wada, Y., Arai-Ichinoi, N., Sakamoto, O., Tamiya, G., Kure, S. The prevalence of GALM mutations that cause galactosemia: a database of functionally evaluated variants. Molec. Genet. Metab. 126: 362-367, 2019. [PubMed: 30910422] [Full Text: https://doi.org/10.1016/j.ymgme.2019.01.018]
Thoden, J. B., Timson, D. J., Reece, R. J., Holden, H. M. Molecular structure of human galactose mutarotase. J. Biol. Chem. 279: 23431-23437, 2004. [PubMed: 15026423] [Full Text: https://doi.org/10.1074/jbc.M402347200]
Timson, D. J., Reece, R. J. Identification and characterisation of human aldose 1-epimerase. FEBS Lett. 543: 21-24, 2003. [PubMed: 12753898] [Full Text: https://doi.org/10.1016/s0014-5793(03)00364-8]
Wada, Y., Kikuchi, A., Arai-Ichinoi, N., Sakamoto, O., Takezawa, Y., Iwasawa, S., Niihori, T., Nyuzuki, H., Nakajima, Y., Ogawa, E., Ishige, M., Hirai, H., and 12 others. Biallelic GALM pathogenic variants cause a novel type of galactosemia. Genet. Med. 21: 1286-1294, 2019. Note: Erratum: Genet. Med. 22: 1281 only, 2020. [PubMed: 30451973] [Full Text: https://doi.org/10.1038/s41436-018-0340-x]