Alternative titles; symbols
HGNC Approved Gene Symbol: GALC
SNOMEDCT: 189979005, 192782005; ICD10CM: E75.23;
Cytogenetic location: 14q31.3 Genomic coordinates (GRCh38) : 14:87,933,014-87,993,667 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q31.3 | Krabbe disease | 245200 | Autosomal recessive | 3 |
Galactosylceramidase (EC 3.2.1.46) is a lysosomal enzyme involved in the catabolism of galactosylceramide, a major lipid in myelin, kidney, and epithelial cells of the small intestine and colon (Chen et al., 1993).
Chen et al. (1993) cloned the human GALC cDNA by screening human testes and human brain cDNA libraries with a degenerate primer derived from a GALC fragment previously isolated from human urine and brain (Chen and Wenger, 1993). Two overlapping clones containing the total protein coding region were obtained. The open reading frame codes for 669 amino acids, representing a protein with a molecular mass of approximately 73 kD.
Sakai et al. (1994) purified galactocerebrosidase from human lymphocytes and cloned the corresponding cDNA. The cDNA encodes a single chain peptide with a 26-amino acid N-terminal signal peptide and 6 potential asparagine-linked glycosylation sites.
Victoria et al. (1996) cloned the canine GALC cDNA and demonstrated that the deduced amino acid sequence is about 90% identical to that of the human protein.
Luzi et al. (1997) described the cloning of the GALC cDNA and gene from the rhesus monkey. The gene organization was nearly identical to that of the human gene, and the deduced amino acid sequence of monkey GALC was about 97%, 87%, and 83% identical to that in human, dog, and mouse, respectively.
Tappino et al. (2010) noted that translation initiation at alternative ATG codons in GALC give rise to protein precursors with 42-residue and 26-residue leader sequences, respectively. Both precursors are processed to the 669-residue mature enzyme.
Luzi et al. (1995) determined that the human GALC gene contains 17 exons spanning about 60 kb of genomic DNA. GALC has a GC-rich promoter region similar to the genes of other lysosomal proteins.
By isotopic in situ hybridization, Cannizzaro et al. (1994) mapped the GALC gene to chromosome 14q31.
By combining genetic perturbation of sphingolipid metabolism with quantification of TLR (see 601194) signaling steps and mass spectrometry-based lipidomics in mouse cells, Koberlin et al. (2015) uncovered a circular network of coregulated sphingolipids and glycerophospholipids. Quantitative lipidomics on fibroblasts from patients with mutations in GBA (606463), GALC, ASAH1 (613468), or LYST (606897) revealed conservation of the circular organization of lipid coregulation across species, cell types, and genetic perturbations. The functional annotation accurately predicted TLR-mediated inflammatory responses, in terms of changes in lipid abundance and lipid species, in patient cells.
Sakai et al. (1994) identified homozygosity for a nonsense mutation (E385X; 606890.0001) in a patient with typical Krabbe disease (KRB; 245200).
Rafi et al. (1995) analyzed the GALC gene in 2 patients with infantile Krabbe disease and identified homozygosity for a 30-kb deletion (606890.0002) that was found to be associated with a 502C-T transition on the same allele, which they designated '502/del.' The transition was determined to be a polymorphism. Expression of the 502/del mutation in COS-1 cells resulted in no measurable GALC activity above that in mock-transfected cells. Rafi et al. (1995) studied an additional 46 patients with infantile Krabbe disease and identified 8 who were homozygous for the 502/del allele and 5 who were compound heterozygotes for the 502/del allele and a second mutant allele, the latter including 3 missense mutations and 1 single nucleotide insertion which had not yet been confirmed by expression studies. The authors noted that 11 patients did not have the 502 polymorphism, but that no patient was found with the deletion who did not carry the 502 polymorphism.
De Gasperi et al. (1996) analyzed the galactocerebrosidase gene in 9 families with late-onset globoid cell leukoencephalopathy (GLD) and in 1 patient with classic Krabbe disease. They reported that 5 of the patients were compound heterozygotes for the 30-kb deletion (606890.0002) first reported by Rafi et al. (1995) and another mutation in the GALC gene. De Gasperi et al. (1996) identified 6 missense mutations: R63H, G95S, M101L, G268S, Y298C, and I234T. They also identified a nonsense mutation (S7X), a 1-bp deletion mutation (805delG), a mutation that interferes with splicing of intron 1, and a 34-nucleotide insertion in the RNA caused by the aberrant splicing of intron 6. Most of the novel mutations identified appeared to be private family mutations. In an erratum, De Gasperi et al. (1996) stated that the loss of a restriction site in exon 8 of the GALC gene in families 2 and 3 with GLD was not due to the 805delG substitution but to an 809G-A transition resulting in a G270D missense mutation; the 805delG substitution identified in 1 member of family 2 led to loss of the same restriction site but the significance of the change was uncertain.
In 2 different inbred communities in Israel with Krabbe disease, Rafi et al. (1996) identified 2 different founder mutations in the GALC gene: one in a Moslem Arab population (606890.0003) and one in a Druze population (606890.0004).
In 4 Japanese patients with adult-onset Krabbe disease, Furuya et al. (1997) identified 4 novel mutations in the GALC gene.
Xu et al. (2006) investigated mutations of the GALC gene in 17 unrelated Japanese patients with Krabbe disease and reviewed the mutations previously reported in 11 Japanese patients. The authors found that 12del3ins and I66M + I289V, which had been identified only in Japanese individuals to date, accounted for 37% of the mutant alleles; with 2 additional mutations, G270D and T652P, these accounted for up to 57% of mutations in Japanese patients. Xu et al. (2006) observed a tendency for the I66M + I289V, G270D, and L618S mutations to be associated with a mild phenotype.
Among 30 unrelated Italian patients with Krabbe disease, Tappino et al. (2010) identified 33 different mutations in the GALC gene, including 14 novel mutations (see, e.g., 606890.0005-606890.0009). The 15 novel mutations included 4 missense mutations in highly conserved residues, 7 frameshift mutations, 3 nonsense mutations, and 1 splice site mutation. Thus, 73% of the newly described mutations were expected to affect mRNA processing. In silico analysis predicted that the missense mutations had a high probability of being deleterious. The common 30-kb deletion (606890.0002) accounted for 18% of mutant alleles, and 4 patients had a founder mutation (G553R; 606890.0005). Otherwise, most of the mutations were private. There were no clear genotype-phenotype correlations, but some missense mutations were associated with milder phenotypes (see, e.g., G286D; 606890.0008).
Victoria et al. (1996) found that the disease-causing mutation in the canine GALC gene was demonstrated to be an A-to-C transversion at cDNA position 473 (Y158S).
Luzi et al. (1997) found that the mutation causing GLD in the rhesus monkey was a deletion of AC corresponding to cDNA positions 387 and 388 in exon 4. This resulted in a frameshift and stop codon after 46 nucleotides. Using an engineered sense primer and an antisense primer from intron 4, Luzi et al. (1997) developed a rapid method to detect the GALC mutation. When 45 monkeys from 1 colony were tested, 22 were found to be carriers. The availability of this nonhuman primate model of GLD provides unique opportunities to evaluate treatment for this severe disease.
In a patient with typical Krabbe disease (KRB; 245200), Sakai et al. (1994) identified homozygosity for a GAA-to-TAA mutation in codon 385, predicting a glu385-to-ter (E385X) substitution. This mutation, originally reported as GLU369TER, has been renumbered based on the first ATG initiation codon as nucleotide +1 (Tappino et al., 2010).
Rafi et al. (1995) analyzed the GALC gene in 2 patients with infantile Krabbe disease and identified homozygosity for a deletion of exons 11-17 that was found to be associated with a 502C-T transition on the same allele, which they designated '502/del.' The transition was later determined to be a polymorphism. Expression of the 502/del mutation in COS-1 cells resulted in no measurable GALC activity above that in mock-transfected cells. Rafi et al. (1995) studied an additional 46 patients with infantile Krabbe disease and identified 8 who were homozygous for the 502/del allele and 5 who were compound heterozygotes for 502/del allele and a second mutant allele. There were 21 patients who were heterozygous and 1 who was homozygous for the 502 polymorphism in whom the presence of the deletion could not be confirmed, but no patient was found with the deletion who did not carry the 502 polymorphism. Luzi et al. (1995) determined that the deletion is approximately 30 kb starting near the middle of intron 10 and including all of the coding region through exon 17 plus an additional 9 kb.
De Gasperi et al. (1996) analyzed the GALC gene in 9 families with late-onset globoid cell leukoencephalopathy and in 1 patient with classic Krabbe disease and found that 5 of the patients were compound heterozygotes for the 30-kb deletion first reported by Rafi et al. (1995) and another mutation in the GALC gene.
Kleijer et al. (1997) found that the 30-kb deletion was present in 52% of mutant alleles from 41 Dutch patients with Krabbe disease.
Tappino et al. (2010) found the 30-kb deletion in 18% of disease alleles among their cohort of 30 Italian patients. They stated that the 502C-T transition has been renumbered as 550C-T based on the first ATG initiation codon as nucleotide +1.
In affected individuals from an inbred Arab Israeli population with infantile Krabbe disease (KRB; 245200), Rafi et al. (1996) identified a homozygous 1630G-A transition in exon 14 of the GALC gene, resulting in an asp544-to-asn (D544N) substitution in the 30-kD subunit. The findings were consistent with a founder effect. In vitro functional expression studies showed that the mutant protein had no enzymatic activity. This mutation, originally reported as ASP528ASN, has been renumbered based on the first ATG initiation codon as nucleotide +1 (Tappino et al., 2010).
In affected individuals from an inbred Druze population in northern Israel with infantile Krabbe disease (KRB; 245200), Rafi et al. (1996) identified a homozygous 1796T-G transversion in exon 15 of the GALC gene, resulting in an ile599-to-ser (I599S) substitution in the 30-kD subunit. The findings were consistent with a founder effect. In vitro functional expression studies showed that the mutant protein had no enzymatic activity. This mutation, originally reported as ILE583SER, has been renumbered based on the first ATG initiation codon as nucleotide +1 (Tappino et al., 2010).
In patients with Krabbe disease (KRB; 245200), Tappino et al. (2010) identified a 1657G-A transition in exon 14 of the GALC gene, resulting in a gly553-to-arg (G553R) substitution. The G553R mutation was found in 7 Italian patients from southern Italy, and haplotype analysis indicated a founder effect.
In an Italian patient with classic Krabbe disease (KRB; 245200), Tappino et al. (2010) identified compound heterozygosity for 2 mutations in the GALC gene: a G-to-A transition (1489+1G-A) in intron 13, demonstrated to cause partial skipping of exon 13 and premature termination, and a 1-bp deletion (1901delT; 606890.0007), also predicted to result in premature termination. The patient presented at age 5 months with truncal hypotonia, hypertonia, spasticity, and white matter changes. Residual GALC activity was 9.7% of control levels.
For discussion of the 1-bp deletion (1901delT) in the GALC gene that was identified in compound heterozygous state in a patient with Krabbe disease (KRB; 245200) by Tappino et al. (2010), see 606890.0006.
In an Italian patient with juvenile onset of Krabbe disease (KRB; 245200) at age 4 years, Tappino et al. (2010) identified compound heterozygosity for 2 mutations in the GALC gene: an 857G-A transition in exon 8, resulting in a gly286-to-asp (G286D) substitution in a highly conserved residue, and the common 30-kb deletion (606890.0002). An unrelated patient with onset of Krabbe disease at age 26 was compound heterozygous for the G286D mutation and a 953C-G transversion in exon 9, resulting in a pro318-to-arg (P318R; 606890.0009) substitution in a highly conserved residue. Tappino et al. (2010) speculated that the G286D mutation may be a mild lesion resulting in a less severe phenotype.
See 606890.0008 and Tappino et al. (2010)
Fiumara et al. (2011) identified a 121G-A transition in the GALC gene, resulting in a gly41-to-ser (G41S) substitution, as a founder mutation for Krabbe disease (KRB; 245200) among Sicilian Italians from the region of Catania. The mutation was enriched among 17 patients with onset of disease after age 6 months. Among the 4 patients who were homozygous for the mutation, enzyme activity ranged between 1 and 6% of controls, but there was no correlation between enzyme activity and age at onset or disease course. However, Fiumara et al. (2011) concluded that the G41S mutation is associated with a protracted course of the disorder, although patients were significantly disabled.
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