NA04517
DNA from Fibroblast
Description:
KRABBE DISEASE
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases
Lysosomal Storage Diseases |
| Class |
Disorders of Lipid Metabolism |
| Quantity |
10 µg |
| Quantitation Method |
Please see our FAQ |
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Cell Type
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Fibroblast
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Transformant
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Untransformed
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Sample Source
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DNA from Fibroblast
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Race
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White
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Relation to Proband
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proband
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Confirmation
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Molecular characterization after cell line submission to CCR
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| PDL at Freeze |
2.26 |
| Passage Frozen |
4 |
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis |
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| galactosylceramidase |
According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.2.1.46 |
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| galactosylceramidase |
According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.2.1.46 |
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| Gene |
GALC |
| Chromosomal Location |
14q24.3-q32.1 |
| Allelic Variant 1 |
606890.0002; KRABBE DISEASE, INFANTILE |
| Identified Mutation |
30-KB DEL, IVS10; Rafi et al. (1995) stated that although most patients with globoid cell leukodystrophy have the severe infantile form, patients up to 50 years of age have been diagnosed in their laboratory. They reported that a large deletion, together with a polymorphic C-to-T transition at position 502 of the cDNA (counting from the A of the initiation codon), was responsible for a large number of disease-causing alleles in patients with Krabbe disease. Of 48 patients evaluated, 10 were found to be homozygous for the 502/del allele, 5 were heterozygous for this allele, 21 were heterozygous for the 502 mutation (presence of the deletion could not be confirmed), and 1 infantile patient was homozygous for the 502 mutation but at least 1 allele was not deleted. No patient was found to have the deletion without the 502 mutation. The deletion of the entire coding region located beyond exon 10 was first detected by failure to PCR amplify any cDNA sequences from that part of the gene. Intron 10 is the largest intron in the GALC gene and is estimated to be about 12 kb in length. In the patients with deletions, PCR amplification was successful for detecting only about 5 kb into intron 10. The large deletions starting within intron 10 result in the loss of coding information from 7 exons which represent about 15% of the 50-kD subunit and all of the 30-kD subunit. Normally, these 2 subunits are produced from the 80-kD precursor protein (Chen and Wenger, 1993). The occurrence of the deletion on the 502 allele and not on the normal allele indicates that the deletion event may have happened only once. The large deletion occurred particularly in patients with infantile Krabbe disease who have northern European ancestry; however, 1 homozygous patient had a Hispanic surname. Since more people have the 502 mutation and are carriers of classic Krabbe disease, it must be a polymorphism. However, the change from arginine to cysteine could result in improper folding of the GALC subunits due to abnormal disulfide bond formation.
In a study of 64 unrelated patients with infantile Krabbe disease of Dutch (n = 41) or other European (n = 23) origin, Kleijer et al. (1997) found the large 30-kb deletion starting in intron 10 in 52% of the 82 GALC Dutch alleles and in 35% of the non-Dutch alleles. The 502T polymorphism, which had an allele frequency of 5.3% in a Dutch control panel, occurred in 65% of the GLD alleles. Analysis of patients and both parents in 26 of the Dutch families showed that the 30-kb deletion was invariably associated with 502T. However, 502T was also present on 40% of the GLD alleles with an as yet unidentified mutation, which is 7.5 times higher than its frequency in controls. This suggested that in addition to the 30-kb deletion, at least 1 other relatively frequent mutation had arisen on the the 502T GALC allele. See also 245200.0007.
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| Gene |
GALC |
| Chromosomal Location |
14q24.3-q32.1 |
| Allelic Variant 2 |
606890.0002; KRABBE DISEASE, INFANTILE |
| Identified Mutation |
30-KB DEL, IVS10; Rafi et al. (1995) stated that although most patients with globoid cell leukodystrophy have the severe infantile form, patients up to 50 years of age have been diagnosed in their laboratory. They reported that a large deletion, together with a polymorphic C-to-T transition at position 502 of the cDNA (counting from the A of the initiation codon), was responsible for a large number of disease-causing alleles in patients with Krabbe disease. Of 48 patients evaluated, 10 were found to be homozygous for the 502/del allele, 5 were heterozygous for this allele, 21 were heterozygous for the 502 mutation (presence of the deletion could not be confirmed), and 1 infantile patient was homozygous for the 502 mutation but at least 1 allele was not deleted. No patient was found to have the deletion without the 502 mutation. The deletion of the entire coding region located beyond exon 10 was first detected by failure to PCR amplify any cDNA sequences from that part of the gene. Intron 10 is the largest intron in the GALC gene and is estimated to be about 12 kb in length. In the patients with deletions, PCR amplification was successful for detecting only about 5 kb into intron 10. The large deletions starting within intron 10 result in the loss of coding information from 7 exons which represent about 15% of the 50-kD subunit and all of the 30-kD subunit. Normally, these 2 subunits are produced from the 80-kD precursor protein (Chen and Wenger, 1993). The occurrence of the deletion on the 502 allele and not on the normal allele indicates that the deletion event may have happened only once. The large deletion occurred particularly in patients with infantile Krabbe disease who have northern European ancestry; however, 1 homozygous patient had a Hispanic surname. Since more people have the 502 mutation and are carriers of classic Krabbe disease, it must be a polymorphism. However, the change from arginine to cysteine could result in improper folding of the GALC subunits due to abnormal disulfide bond formation.
In a study of 64 unrelated patients with infantile Krabbe disease of Dutch (n = 41) or other European (n = 23) origin, Kleijer et al. (1997) found the large 30-kb deletion starting in intron 10 in 52% of the 82 GALC Dutch alleles and in 35% of the non-Dutch alleles. The 502T polymorphism, which had an allele frequency of 5.3% in a Dutch control panel, occurred in 65% of the GLD alleles. Analysis of patients and both parents in 26 of the Dutch families showed that the 30-kb deletion was invariably associated with 502T. However, 502T was also present on 40% of the GLD alleles with an as yet unidentified mutation, which is 7.5 times higher than its frequency in controls. This suggested that in addition to the 30-kb deletion, at least 1 other relatively frequent mutation had arisen on the the 502T GALC allele. See also 245200.0007.
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| Remarks |
Developmental delay; seizures and spasticity; deficient galactocerebrosidase activity in WBC; fibroblasts show a deficiency of taurocholate activated galactosylceramidase; donor subject is homozygous for a 30 kb deletion beginning near the middle of intron 10 in the GALC gene resulting in the loss of the sequences encoded by exons 11-17 plus an additional 9 kb |
| Li Y, Xu Y, Benitez BA, Nagree MS, Dearborn JT, Jiang X, Guzman MA, Woloszynek JC, Giaramita A, Yip BK, Elsbernd J, Babcock MC, Lo M, Fowler SC, Wozniak DF, Vogler CA, Medin JA, Crawford BE, Sands MS, Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target Proceedings of the National Academy of Sciences of the United States of America116:20097-20103 2019 |
| PubMed ID: 31527255 |
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| Andrew M. Gross PhD, Subramanian S. Ajay PhD, Vani Rajan MS, Carolyn Brown CGC, Krista Bluske PhD, Nicole J. Burns MS, Aditi Chawla PhD, Alison J. Coffey PhD, Alka Malhotra PhD, Alicia Scocchia MS CGC, Erin Thorpe MS CGC, Natasa Dzidic MS, Karine Hovanes PhD FACMG, Trilochan Sahoo MD FACMG, Egor Dolzhenko PhD, Bryan Lajoie PhD, Amirah Khouzam MS CGC, Shimul Chowdhury PhD FACMG, John Belmont MD PhD, Eric Roller PhD, Sergii Ivakhno PhD, Stephen Tanner PhD, Julia McEachern PA MHS, Tina Hambuch PhD FACMG, Michael Eberle PhD, R. Tanner Hagelstrom PhD FACMG, David R. Bentley PhD, Denise L. Perry MS CGC & Ryan J. Taft PhD, Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease Genetics in Medicine116:20097-20103 2018 |
| PubMed ID: 30293986 |
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| Kobayashi T, Shinnoh N, Goto I, Kuroiwa Y, Hydrolysis of galactosylceramide is catalyzed by two genetically distinct acid beta-galactosidases. J Biol Chem260:14982-7 1985 |
| PubMed ID: 3934152 |
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| Kobayashi T, Shinnoh N, Goto I, Kuroiwa Y, Okawauchi M, Sugihara G, Tanaka M, Galactosylceramide- and lactosylceramide-loading studies in cultured fibroblasts from normal individuals and patients with globoid cell leukodystrophy (Krabbe's disease) and GM1-gangliosidosis. Biochim Biophys Acta835:456-64 1985 |
| PubMed ID: 3926002 |
| dbSNP |
dbSNP ID: 18665 |
| NCBI GTR |
245200 KRABBE DISEASE |
| OMIM |
245200 KRABBE DISEASE |
| Omim Description |
GALACTOCEREBROSIDASE DEFICIENCY |
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GALACTOSYLCERAMIDE BETA-GALACTOSIDASE DEFICIENCY |
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GALC DEFICIENCYGALACTOSYLCERAMIDASE, INCLUDED; GALC, INCLUDED |
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GLOBOID CELL LEUKODYSTROPHY; GLD; GCL |
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GLOBOID CELL LEUKOENCEPHALOPATHY |
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KRABBE DISEASE |
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