HGNC Approved Gene Symbol:GGT1
Cytogenetic location:22q11.23 Genomic coordinates(GRCh38) :22:24,583,750-24,628,996 (from NCBI)
GGT1 belongs to the gamma-glutamyltransferase (GGT;EC 2.3.2.2) gene family. GGT is a membrane-bound extracellular enzyme that cleaves gamma-glutamyl peptide bonds in glutathione and other peptides and transfers the gamma-glutamyl moiety to acceptors. GGT is also key to glutathione homeostasis because it provides substrates for glutathione synthesis. Autocatalytic cleavage of the GGT1 precursor polypeptide produces a heavy chain and a light chain that associate with each other to form the functional enzyme (Heisterkamp et al., 2008).
See231950 for information on GGT deficiency; see also GGTQLT1 (612365) and GGTQLT2 (612366) for information on quantitative trait loci associated with the plasma level of gamma glutamyltransferase.
Laperche et al. (1986) cloned the structural gene for Ggt from a rat kidney cDNA library.
Rajpert-De Meyts et al. (1988) isolated cDNAs for human GGT.Sakamuro et al. (1988) reported the primary structure of human GGT based on studies of a cDNA. The enzyme consists of 2 peptide chains, heavy and light, composed of 351 and 189 amino acids, respectively. The 2 subunits of the mature enzyme are the products of processing of a single precursor peptide encoded by the GGT gene. The active site of GGT is located in the light subunit of the mature enzyme.
Wetmore et al. (1993) stated that GGT1 is anchored in the plasma membrane by an N-terminal transmembrane domain in the heavy subunit. Catalytic activity toward gamma-glutamyl substrates requires thr523 in the light subunit and lys99 and arg111 in the heavy subunit.Heisterkamp et al. (2008) noted that the glutamate-binding site of GGT1 includes 8 residues in its light chain and 1 residue (arg107) in its heavy chain.
Wetmore et al. (1993) andLeh et al. (1998) reported a short GGT1 splice variant that was specifically expressed in lung.Heisterkamp et al. (2008) stated that there are several alternatively spliced GGT1 transcripts, including the short lung-specific mRNA that is initiated from a promoter in intron 7.
By PCR analysis,Courtay et al. (1994) detected expression of GGT1, which they called clone 6, in all adult and fetal tissues examined.Leh et al. (1996) detected GGT1 expression in lymphocytes from healthy subjects and patients with acute lymphoblastic leukemia, as well as in all hematopoietic cell lines examined.
Leh et al. (1998) determined that the GGT1 gene contains 12 exons and spans more than 16 kb. Intron 7 is 3.9 kb and contains a functional alternative promoter. This promoter has a TATA-like region, but no CAAT boxes. It also has a GT motif homologous to the core sequence of many enhancers.
Bulle et al. (1987) mapped the GGT gene by in situ hybridization to chromosome 22q11.1-q11.2. A minor peak was found in chromosome 22q13.1.Rouleau et al. (1988) demonstrated a PvuII polymorphism at the GGT locus and added family linkage analysis to the methods by which GGT had been assigned to chromosome 22. From studies involving restriction analysis,Heisterkamp and Groffen (1988) presented evidence that the transcribed GGT gene lies 3-prime and just distal to the BCR locus (151410).
A family of at least 4 GGT genes exists on chromosome 22 (Pawlak et al., 1988;Rajpert-De Meyts et al., 1988). At least 2 of these genes appear to be transcribed, since a human kidney cDNA has been isolated that differs from the placenta and liver cDNAs (Pawlak et al., 1989).
Using somatic cell hybrids for hybridization with probes from a human kidney GGT cDNA clone and by amplification of a 3-prime GGT sequence by PCR,Figlewicz et al. (1993) characterized the GGT gene-pseudogene family further. They clearly mapped 3 GGT loci to chromosome 22: 2 loci (GGT1 and GGT2,137181) between the centromere and BCR, and 1 locus telomeric to BCR. In addition, they identified GGT-related sequences on chromosomes 18, 19, and 20.
By searching human genomic and cDNA databases for sequences related to GGT1,Heisterkamp et al. (2008) identified 13 genes belonging to the GGT family. Five genes have the potential to encode precursor proteins containing heavy chain and light chain regions: GGT1, GGT2, and GGT5 (137168) on chromosome 22q11.2, GGT6 (612341) on chromosome 17p13.2, and GGT7 (612342) on chromosome 20q11.2. Three genes have the potential to encode only the light chain portion of GGT1: GGTLC1 (612338) on chromosome 20p11.1 and GGTLC2 (612339) and GGTLC3 (612340) on chromosome 22q11.2. The remaining 5 genes are pseudogenes: GGT3P, GGTLC4P, and GGTLC5P on chromosome 22q11.2, GGT4P on chromosome 13, GGT8P on chromosome 2p11.1.
Glutathionuria
In 2 Turkish sibs with glutathionuria,Darin et al. (2018) identified a homozygous 16,993-bp deletion combined with a 13-bp insertion (612346.0001) in the GGT1 gene that removed the first coding exon and several noncoding exons in all isoforms of GGT1. Both parents were heterozygous for this deletion. Both deletion breakpoints were located in Alu elements.
Associations Pending Confirmation
For discussion of a possible association between a SNP in the GGT1 gene and plasma levels of GGT, see612365.
Ggt1 dwg/dwg mice are spontaneous mutant mice with a nucleotide deletion in the Ggt1 gene and are characterized by dwarfism, cataract, and coat color abnormality.Yamada et al. (2013) found that Ggt1 dwg/dwg mice had higher levels of glutathione (GSH) in plasma and kidney, but lower levels in liver and eye, compared with wildtype mice. Ggt1 dwg/dwg mice were indistinguishable in appearance from their normal littermates at birth, but they showed slow growth from 3 weeks to 9 weeks of age, resulting in lower body length and weight at 9 weeks of age compared with wildtype littermates. Histologic analysis of Ggt1 dwg/dwg mice revealed small vacuoles near lens epithelium at 3 weeks of age. At 9 weeks of age, the vacuoles were swollen around the nuclear and cortical regions, and most lens fibers were degenerated. Increased numbers of osteoclasts were also observed in Gg1 dwg/dwg mice. The authors concluded that the phenotypic alterations in Ggt1 dwg/dwg mice were due to GSH deficiency, because the observed phenotypes were completely or partially reversed by N-acetyl-L-cysteine treatment.
In 2 sibs with glutathionuria (231950), born of consanguineous Turkish parents,Darin et al. (2018) detected homozygosity for a 16,993-bp deletion/13-bp insertion in the GGT1 gene that removed the first coding exon and several noncoding exons of all isoforms of GGT1. The mutation was detected by whole-genome sequencing. The deletion breakpoints were chr22.24,992,587 (centromere) and chr22.25,009,579 (telomere).
Bulle, F., Mattei, M. G., Siegrist, S., Pawlak, A., Passage, E., Chobert, M. N., Laperche, Y., Guellaen, G.Assignment of the human gamma-glutamyl transferase gene to the long arm of chromosome 22. Hum. Genet. 76: 283-286, 1987. [PubMed:2885259,related citations] [Full Text]
Courtay, C., Heisterkamp, N., Siest, G., Groffen, J.Expression of multiple gamma-glutamyltransferase genes in man. Biochem. J. 297: 503-508, 1994. [PubMed:7906515,related citations] [Full Text]
Darin, N., Leckstrom, K., Sikora, P., Lindgren, J., Almen, G., Asin-Cayuela, J.Gamma-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1. Europ. J. Hum. Genet. 26: 808-817, 2018. [PubMed:29483667,related citations] [Full Text]
Figlewicz, D. A., Delattre, O., Guellaen, G., Krizus, A., Thomas, G., Zucman, J., Rouleau, G. A.Mapping of human gamma-glutamyl transpeptidase genes on chromosome 22 and other human autosomes. Genomics 17: 299-305, 1993. [PubMed:8104871,related citations] [Full Text]
Heisterkamp, N., Groffen, J., Warburton, D., Sneddon, T. P.The human gamma-glutamyltransferase gene family. Hum. Genet. 123: 321-332, 2008. [PubMed:18357469,related citations] [Full Text]
Heisterkamp, N., Groffen, J.Duplication of the bcr and gamma-glutamyl transpeptidase genes. Nucleic Acids Res. 16: 8045-8056, 1988. [PubMed:2901712,related citations] [Full Text]
Laperche, Y., Bulle, F., Aissani, T., Chobert, M. N., Aggerbeck, M., Hanoune, J., Guellaen, G.Molecular cloning and nucleotide sequence of rat kidney gamma-glutamyl transpeptidase cDNA. Proc. Nat. Acad. Sci. 83: 937-941, 1986. Note: Erratum: Proc. Nat. Acad. Sci. 86: 3159 only, 1989. [PubMed:2869484,related citations] [Full Text]
Leh, H., Chikhi, N., Ichino, K., Guellaen, G., Wellman, M., Siest, G., Visvikis, A.An intronic promoter controls the expression of truncated human gamma-glutamyltransferase mRNAs. FEBS Lett. 434: 51-56, 1998. [PubMed:9738450,related citations] [Full Text]
Leh, H., Courtay, C., Gerardin, P., Wellman, M., Siest, G., Visvikis, A.Cloning and expression of a novel type (III) of human gamma-glutamyltransferase truncated mRNA. FEBS Lett. 394: 258-262, 1996. [PubMed:8830654,related citations] [Full Text]
Pawlak, A., Lahuna, O., Bulle, F., Suzuki, A., Ferry, N., Siegrist, S., Chikhi, N., Chobert, M. N., Guellaen, G., Laperche, Y.Gamma-glutamyl transpeptidase: a single copy gene in the rat and a multigene family in the human genome. J. Biol. Chem. 263: 9913-9916, 1988. [PubMed:2898474,related citations]
Pawlak, A., Wu, S.-J., Bulle, F., Suzuki, A., Chikhi, N., Ferry, N., Baik, J.-H., Siegrist, S., Guellaen, G.Different gamma-glutamyl transpeptidase mRNAs are expressed in human liver and kidney. Biochem. Biophys. Res. Commun. 164: 912-918, 1989. [PubMed:2573352,related citations] [Full Text]
Rajpert-De Meyts, E., Heisterkamp, N., Groffen, J.Cloning and nucleotide sequence of human gamma-glutamyl transpeptidase. Proc. Nat. Acad. Sci. 85: 8840-8844, 1988. [PubMed:2904146,related citations] [Full Text]
Rouleau, G. A., Bazanowski, A., Cohen, E. H., Guellaen, G., Gusella, J. F.Gamma-glutamyl transferase locus (GGT) displays a PvuII polymorphism. Nucleic Acids Res. 16: 11848 only, 1988. [PubMed:2905445,related citations] [Full Text]
Sakamuro, D., Yamazoe, M., Matsuda, Y., Kangawa, K., Taniguchi, N., Matsuo, H., Yoshikawa, H., Ogasawara, N.The primary structure of human gamma-glutamyl transpeptidase. Gene 73: 1-9, 1988. [PubMed:2907498,related citations] [Full Text]
Wetmore, L. A., Gerard, C., Drazen, J. M.Human lung expresses unique gamma-glutamyl transpeptidase transcripts. Proc. Nat. Acad. Sci. 90: 7461-7465, 1993. [PubMed:7689219,related citations] [Full Text]
Yamada, K., Tsuji, T., Kunieda, T.Phenotypic characterization of Ggt1(dwg/dwg) mice, a mouse model for hereditary gamma-glutamyl transferase deficiency. Exp. Anim. 62: 151-157, 2013. [PubMed:23615310,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: GGT1
SNOMEDCT: 78586005;
Cytogenetic location: 22q11.23 Genomic coordinates(GRCh38) : 22:24,583,750-24,628,996(from NCBI)
| Location | Phenotype | Phenotype MIM number | Inheritance | Phenotype mapping key |
|---|---|---|---|---|
| 22q11.23 | ?Glutathioninuria | 231950 | Autosomal recessive | 3 |
GGT1 belongs to the gamma-glutamyltransferase (GGT; EC 2.3.2.2) gene family. GGT is a membrane-bound extracellular enzyme that cleaves gamma-glutamyl peptide bonds in glutathione and other peptides and transfers the gamma-glutamyl moiety to acceptors. GGT is also key to glutathione homeostasis because it provides substrates for glutathione synthesis. Autocatalytic cleavage of the GGT1 precursor polypeptide produces a heavy chain and a light chain that associate with each other to form the functional enzyme (Heisterkamp et al., 2008).
See 231950 for information on GGT deficiency; see also GGTQLT1 (612365) and GGTQLT2 (612366) for information on quantitative trait loci associated with the plasma level of gamma glutamyltransferase.
Laperche et al. (1986) cloned the structural gene for Ggt from a rat kidney cDNA library.
Rajpert-De Meyts et al. (1988) isolated cDNAs for human GGT. Sakamuro et al. (1988) reported the primary structure of human GGT based on studies of a cDNA. The enzyme consists of 2 peptide chains, heavy and light, composed of 351 and 189 amino acids, respectively. The 2 subunits of the mature enzyme are the products of processing of a single precursor peptide encoded by the GGT gene. The active site of GGT is located in the light subunit of the mature enzyme.
Wetmore et al. (1993) stated that GGT1 is anchored in the plasma membrane by an N-terminal transmembrane domain in the heavy subunit. Catalytic activity toward gamma-glutamyl substrates requires thr523 in the light subunit and lys99 and arg111 in the heavy subunit. Heisterkamp et al. (2008) noted that the glutamate-binding site of GGT1 includes 8 residues in its light chain and 1 residue (arg107) in its heavy chain.
Wetmore et al. (1993) and Leh et al. (1998) reported a short GGT1 splice variant that was specifically expressed in lung. Heisterkamp et al. (2008) stated that there are several alternatively spliced GGT1 transcripts, including the short lung-specific mRNA that is initiated from a promoter in intron 7.
By PCR analysis, Courtay et al. (1994) detected expression of GGT1, which they called clone 6, in all adult and fetal tissues examined. Leh et al. (1996) detected GGT1 expression in lymphocytes from healthy subjects and patients with acute lymphoblastic leukemia, as well as in all hematopoietic cell lines examined.
Leh et al. (1998) determined that the GGT1 gene contains 12 exons and spans more than 16 kb. Intron 7 is 3.9 kb and contains a functional alternative promoter. This promoter has a TATA-like region, but no CAAT boxes. It also has a GT motif homologous to the core sequence of many enhancers.
Bulle et al. (1987) mapped the GGT gene by in situ hybridization to chromosome 22q11.1-q11.2. A minor peak was found in chromosome 22q13.1. Rouleau et al. (1988) demonstrated a PvuII polymorphism at the GGT locus and added family linkage analysis to the methods by which GGT had been assigned to chromosome 22. From studies involving restriction analysis, Heisterkamp and Groffen (1988) presented evidence that the transcribed GGT gene lies 3-prime and just distal to the BCR locus (151410).
A family of at least 4 GGT genes exists on chromosome 22 (Pawlak et al., 1988; Rajpert-De Meyts et al., 1988). At least 2 of these genes appear to be transcribed, since a human kidney cDNA has been isolated that differs from the placenta and liver cDNAs (Pawlak et al., 1989).
Using somatic cell hybrids for hybridization with probes from a human kidney GGT cDNA clone and by amplification of a 3-prime GGT sequence by PCR, Figlewicz et al. (1993) characterized the GGT gene-pseudogene family further. They clearly mapped 3 GGT loci to chromosome 22: 2 loci (GGT1 and GGT2, 137181) between the centromere and BCR, and 1 locus telomeric to BCR. In addition, they identified GGT-related sequences on chromosomes 18, 19, and 20.
By searching human genomic and cDNA databases for sequences related to GGT1, Heisterkamp et al. (2008) identified 13 genes belonging to the GGT family. Five genes have the potential to encode precursor proteins containing heavy chain and light chain regions: GGT1, GGT2, and GGT5 (137168) on chromosome 22q11.2, GGT6 (612341) on chromosome 17p13.2, and GGT7 (612342) on chromosome 20q11.2. Three genes have the potential to encode only the light chain portion of GGT1: GGTLC1 (612338) on chromosome 20p11.1 and GGTLC2 (612339) and GGTLC3 (612340) on chromosome 22q11.2. The remaining 5 genes are pseudogenes: GGT3P, GGTLC4P, and GGTLC5P on chromosome 22q11.2, GGT4P on chromosome 13, GGT8P on chromosome 2p11.1.
Glutathionuria
In 2 Turkish sibs with glutathionuria, Darin et al. (2018) identified a homozygous 16,993-bp deletion combined with a 13-bp insertion (612346.0001) in the GGT1 gene that removed the first coding exon and several noncoding exons in all isoforms of GGT1. Both parents were heterozygous for this deletion. Both deletion breakpoints were located in Alu elements.
Associations Pending Confirmation
For discussion of a possible association between a SNP in the GGT1 gene and plasma levels of GGT, see 612365.
Ggt1 dwg/dwg mice are spontaneous mutant mice with a nucleotide deletion in the Ggt1 gene and are characterized by dwarfism, cataract, and coat color abnormality. Yamada et al. (2013) found that Ggt1 dwg/dwg mice had higher levels of glutathione (GSH) in plasma and kidney, but lower levels in liver and eye, compared with wildtype mice. Ggt1 dwg/dwg mice were indistinguishable in appearance from their normal littermates at birth, but they showed slow growth from 3 weeks to 9 weeks of age, resulting in lower body length and weight at 9 weeks of age compared with wildtype littermates. Histologic analysis of Ggt1 dwg/dwg mice revealed small vacuoles near lens epithelium at 3 weeks of age. At 9 weeks of age, the vacuoles were swollen around the nuclear and cortical regions, and most lens fibers were degenerated. Increased numbers of osteoclasts were also observed in Gg1 dwg/dwg mice. The authors concluded that the phenotypic alterations in Ggt1 dwg/dwg mice were due to GSH deficiency, because the observed phenotypes were completely or partially reversed by N-acetyl-L-cysteine treatment.
In 2 sibs with glutathionuria (231950), born of consanguineous Turkish parents, Darin et al. (2018) detected homozygosity for a 16,993-bp deletion/13-bp insertion in the GGT1 gene that removed the first coding exon and several noncoding exons of all isoforms of GGT1. The mutation was detected by whole-genome sequencing. The deletion breakpoints were chr22.24,992,587 (centromere) and chr22.25,009,579 (telomere).
Bulle, F., Mattei, M. G., Siegrist, S., Pawlak, A., Passage, E., Chobert, M. N., Laperche, Y., Guellaen, G.Assignment of the human gamma-glutamyl transferase gene to the long arm of chromosome 22. Hum. Genet. 76: 283-286, 1987. [PubMed: 2885259] [Full Text: https://doi.org/10.1007/BF00283624]
Courtay, C., Heisterkamp, N., Siest, G., Groffen, J.Expression of multiple gamma-glutamyltransferase genes in man. Biochem. J. 297: 503-508, 1994. [PubMed: 7906515] [Full Text: https://doi.org/10.1042/bj2970503]
Darin, N., Leckstrom, K., Sikora, P., Lindgren, J., Almen, G., Asin-Cayuela, J.Gamma-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1. Europ. J. Hum. Genet. 26: 808-817, 2018. [PubMed: 29483667] [Full Text: https://doi.org/10.1038/s41431-018-0122-6]
Figlewicz, D. A., Delattre, O., Guellaen, G., Krizus, A., Thomas, G., Zucman, J., Rouleau, G. A.Mapping of human gamma-glutamyl transpeptidase genes on chromosome 22 and other human autosomes. Genomics 17: 299-305, 1993. [PubMed: 8104871] [Full Text: https://doi.org/10.1006/geno.1993.1325]
Heisterkamp, N., Groffen, J., Warburton, D., Sneddon, T. P.The human gamma-glutamyltransferase gene family. Hum. Genet. 123: 321-332, 2008. [PubMed: 18357469] [Full Text: https://doi.org/10.1007/s00439-008-0487-7]
Heisterkamp, N., Groffen, J.Duplication of the bcr and gamma-glutamyl transpeptidase genes. Nucleic Acids Res. 16: 8045-8056, 1988. [PubMed: 2901712] [Full Text: https://doi.org/10.1093/nar/16.16.8045]
Laperche, Y., Bulle, F., Aissani, T., Chobert, M. N., Aggerbeck, M., Hanoune, J., Guellaen, G.Molecular cloning and nucleotide sequence of rat kidney gamma-glutamyl transpeptidase cDNA. Proc. Nat. Acad. Sci. 83: 937-941, 1986. Note: Erratum: Proc. Nat. Acad. Sci. 86: 3159 only, 1989. [PubMed: 2869484] [Full Text: https://doi.org/10.1073/pnas.83.4.937]
Leh, H., Chikhi, N., Ichino, K., Guellaen, G., Wellman, M., Siest, G., Visvikis, A.An intronic promoter controls the expression of truncated human gamma-glutamyltransferase mRNAs. FEBS Lett. 434: 51-56, 1998. [PubMed: 9738450] [Full Text: https://doi.org/10.1016/s0014-5793(98)00950-8]
Leh, H., Courtay, C., Gerardin, P., Wellman, M., Siest, G., Visvikis, A.Cloning and expression of a novel type (III) of human gamma-glutamyltransferase truncated mRNA. FEBS Lett. 394: 258-262, 1996. [PubMed: 8830654] [Full Text: https://doi.org/10.1016/0014-5793(96)00965-9]
Pawlak, A., Lahuna, O., Bulle, F., Suzuki, A., Ferry, N., Siegrist, S., Chikhi, N., Chobert, M. N., Guellaen, G., Laperche, Y.Gamma-glutamyl transpeptidase: a single copy gene in the rat and a multigene family in the human genome. J. Biol. Chem. 263: 9913-9916, 1988. [PubMed: 2898474]
Pawlak, A., Wu, S.-J., Bulle, F., Suzuki, A., Chikhi, N., Ferry, N., Baik, J.-H., Siegrist, S., Guellaen, G.Different gamma-glutamyl transpeptidase mRNAs are expressed in human liver and kidney. Biochem. Biophys. Res. Commun. 164: 912-918, 1989. [PubMed: 2573352] [Full Text: https://doi.org/10.1016/0006-291x(89)91545-3]
Rajpert-De Meyts, E., Heisterkamp, N., Groffen, J.Cloning and nucleotide sequence of human gamma-glutamyl transpeptidase. Proc. Nat. Acad. Sci. 85: 8840-8844, 1988. [PubMed: 2904146] [Full Text: https://doi.org/10.1073/pnas.85.23.8840]
Rouleau, G. A., Bazanowski, A., Cohen, E. H., Guellaen, G., Gusella, J. F.Gamma-glutamyl transferase locus (GGT) displays a PvuII polymorphism. Nucleic Acids Res. 16: 11848 only, 1988. [PubMed: 2905445] [Full Text: https://doi.org/10.1093/nar/16.24.11848]
Sakamuro, D., Yamazoe, M., Matsuda, Y., Kangawa, K., Taniguchi, N., Matsuo, H., Yoshikawa, H., Ogasawara, N.The primary structure of human gamma-glutamyl transpeptidase. Gene 73: 1-9, 1988. [PubMed: 2907498] [Full Text: https://doi.org/10.1016/0378-1119(88)90307-1]
Wetmore, L. A., Gerard, C., Drazen, J. M.Human lung expresses unique gamma-glutamyl transpeptidase transcripts. Proc. Nat. Acad. Sci. 90: 7461-7465, 1993. [PubMed: 7689219] [Full Text: https://doi.org/10.1073/pnas.90.16.7461]
Yamada, K., Tsuji, T., Kunieda, T.Phenotypic characterization of Ggt1(dwg/dwg) mice, a mouse model for hereditary gamma-glutamyl transferase deficiency. Exp. Anim. 62: 151-157, 2013. [PubMed: 23615310] [Full Text: https://doi.org/10.1538/expanim.62.151]
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