Alternative titles; symbols
HGNC Approved Gene Symbol: NAGA
SNOMEDCT: 238048001, 879937000, 880065001, 880066000;
Cytogenetic location: 22q13.2 Genomic coordinates (GRCh38): 22:42,058,334-42,070,842 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.2 | Kanzaki disease | 609242 | Autosomal recessive | 3 |
| Schindler disease, type I | 609241 | Autosomal recessive | 3 | |
| Schindler disease, type III | 609241 | Autosomal recessive | 3 |
Alpha-N-acetylgalactosaminidase (EC 3.2.1.49) is a lysosomal glycohydrolase that cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates.
Wang et al. (1990) isolated a full-length 2.2-kb NAGA cDNA and a genomic cosmid clone containing the entire NAGA gene from a human fibroblast cDNA library. The cDNA encodes a 411-amino acid protein with a 17-residue signal peptide and 6 putative N-glycosylation sites. Northern blot analysis detected 2 mRNA transcripts of 3.6 and 2.2 kb. Sequence analysis revealed striking similarities between the NAGA gene and exons 1-6 of the alpha-galactosidase A gene (GLA; 300644), suggesting that the 2 genes evolved by duplication and divergence from a common ancestral locus. Wang and Desnick (1991) also pointed to remarkable amino acid identity between the NAGA and GLA genes.
Wang et al. (1998) isolated the mouse Naga cDNA from a fibroblast cDNA library and found that the deduced human and mouse proteins share 81.9% sequence identity.
Wang and Desnick (1991) determined that the NAGA gene contains 9 exons.
De Groot et al. (1978) assigned the human N-acetyl-alpha-D-galactosaminidase gene to chromosome 22 by human-rodent somatic cell hybridization. The authors suggested that 'alpha-NAGA' was a more appropriate designation for this enzyme than alpha-galactosidase B.
In human-rodent cell hybrids, Geurts van Kessel et al. (1979, 1980) studied chronic myeloid leukemia cells to determine the site of the break on 22q relative to markers assigned to chromosomes 22 and 9. Alpha-NAGA remained with the Ph-1 chromosome, whereas the aconitase gene (ACO2; 100850) went with chromosome 9. Alpha-NAGA was located to band 22q11 and ACO2 was located between it and 22qter.
In the first described cases of type I Schindler disease (609241) (van Diggelen et al. (1987, 1988)), Wang et al. (1990) identified a homozygous mutation in the NAGA gene (104170.0001).
In a Japanese woman with Kanzaki disease (609242) reported by Kanzaki et al. (1989), Wang et al. (1990, 1994) identified a homozygous mutation in the NAGA gene (104170.0002).
Wang et al. (1994) generated a mouse model of Schindler disease by targeted disruption of the Naga gene. Naga-null mice appeared clinically normal, survived into adulthood, and were fertile. Consistent with the human disease, the mice had no Naga activity and showed lysosomal pathology, including vacuolated peripheral lymphocytes.
Desnick and Schindler (2001) reported that Naga-null mice developed widespread lysosomal storage of abnormal material in the central nervous system and other organs, as well as focal axonal swellings or spheroids in the brain and spinal cord.
In the 2 German boys first described with Schindler disease (609241) (van Diggelen et al. (1987, 1988)), Wang et al. (1990) identified a homozygous 973G-A transition in exon 8 of the NAGA gene, resulting in a glu325-to-lys (E325K) substitution. Keulemans et al. (1996) identified a distant affected relative of the 2 boys who had the E325K homozygous mutation. The boys had approximately 1% residual NAGA activity.
Bakker et al. (2001) reported homozygosity for the E325K mutation in a 3-year-old Moroccan boy with alpha-NAGA deficiency. He was born of consanguineous parents. The proband and his 7-year-old healthy brother had undetectable alpha-NAGA activity in leukocytes and a profound deficiency in fibroblasts. The parents had alpha-NAGA activity consistent with heterozygosity. Mutation analysis revealed homozygosity for the E325K mutation in the proband and his healthy brother, whereas a third sib and both parents were heterozygous. The family demonstrated the extreme clinical heterogeneity of alpha-NAGA deficiency, as the homozygous brother at the age of 7 years showed no clinical or neurologic symptoms.
In a Japanese woman with disseminated angiokeratoma (609242) reported by Kanzaki et al. (1989), Wang et al. (1990, 1994) identified a homozygous 985C-T transition in the NAGA gene, resulting in an arg329-to-trp (R329W) substitution. The base substitution was confirmed by hybridization of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Wang et al. (1994) showed that in transiently expressed COS-1 cells, both the infantile-onset E325K (104170.0001) and the adult-onset R329W precursors were processed to the mature form; however, the E325K mutant polypeptide was more rapidly degraded than the R329W subunit, thereby providing a basis for the distinctly different infantile- and adult-onset phenotypes.
Keulemans et al. (1996) showed by PCR and sequence analysis that the Spanish brother and sister with manifestations of Kanzaki disease (609242) described by Chabas et al. (1994) were homozygous for a 5371G-T transversion in exon 5 of the NAGA gene (numbering according to Yamauchi et al., 1990), resulting in a glu193-to-ter (E193X) substitution, premature termination, and complete loss of the NAGA protein.
In a Dutch girl with type III NAGA deficiency (609241) reported by de Jong et al. (1994), Keulemans et al. (1996) identified compound heterozygosity for 2 mutations in the NAGA gene: E325K (104170.0001) and a 4969C-G transversion in exon 4 (numbering according to Yamauchi et al., 1990), resulting in a ser160-to-cys (S160C) substitution. The same genotype was found in the clinically unaffected 3-year-old brother of the proband, and the authors suggested that the brother might be a preclinical case of NAGA deficiency; the brother's twin sister did not have the genotype. Residual enzyme activity in the proband was approximately 4% of controls. The S160C allele was not identified in 80 Dutch control alleles.
In a Japanese woman with Kanzaki disease (609242), Kodama et al. (2001) identified a homozygous 986G-A transition in the NAGA gene, resulting in an arg329-to-gln (R329Q) substitution. The patient had angiokeratoma corporis diffusum, Meniere syndrome, and no mental retardation. Her parents were consanguineous.
Bakker, H. D., de Sonnaville, M.-L. C. S., Vreken, P., Abeling, N. G. G. M., Groener, J. E. M., Keulemans, J. L. M., van Diggelen, O. P. Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: no association with neuroaxonal dystrophy? Europ. J. Hum. Genet. 9: 91-96, 2001. [PubMed: 11313741] [Full Text: https://doi.org/10.1038/sj.ejhg.5200598]
Chabas, A., Coll, M. J., Aparicio, M., Rodriguez Diaz, E. Mild phenotypic expression of alpha-N-acetylgalactosaminidase deficiency in two adult siblings. J. Inherit. Metab. Dis. 17: 724-731, 1994. [PubMed: 7707696] [Full Text: https://doi.org/10.1007/BF00712015]
de Groot, P. G., Westerveld, A., Meera Khan, P., Tager, J. M. Localization of a gene for human alpha-galactosidase B (=N-acetyl-alpha-D-galactosaminidase) on chromosome 22. Hum. Genet. 44: 305-312, 1978. [PubMed: 215508] [Full Text: https://doi.org/10.1007/BF00394295]
de Jong, J., van den Berg, C, Wijburg, H., Willemsen, R., van Diggelen, O., Schindler, D., Hoevenaars, F., Wevers, R. Alpha-N-acetylgalactosaminidase deficiency with mild clinical manifestations and difficult biochemical diagnosis. J. Pediat. 125: 385-391, 1994. [PubMed: 8071745] [Full Text: https://doi.org/10.1016/s0022-3476(05)83281-0]
Desnick, R. J., Schindler, D. Alpha-N-acetylgalactosaminidase deficiency: Schindler disease.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. III. (8th ed.) New York: McGraw-Hill (pub.) 2001. Pp. 3483-3505.
Geurts van Kessel, A. H. M., ten Brinke, H., de Groot, P. G., Hagemeijer, A., Westerveld, A., Meera Khan, P., Pearson, P. L. Regional localization of NAGA and ACO2 on human chromosome 22. (Abstract) Cytogenet. Cell Genet. 25: 161 only, 1979.
Geurts van Kessel, A. H. M., Westerveld, A., de Groot, P. G., Meera Khan, P., Hagemeijer, A. Regional localization of the genes coding for human ACO2, ARSA, and NAGA on chromosome 22. Cytogenet. Cell Genet. 28: 169-172, 1980. [PubMed: 7192199] [Full Text: https://doi.org/10.1159/000131527]
Kanzaki, T., Yokota, M., Mizuno, N., Matsumoto, Y., Hirabayashi, Y. Novel lysosomal glycoaminoacid storage disease with angiokeratoma corporis diffusum. Lancet 333: 875-876, 1989. Note: Originally Volume I. [PubMed: 2564952] [Full Text: https://doi.org/10.1016/s0140-6736(89)92867-5]
Keulemans, J. L. M., Reuser, A. J. J., Kroos, M. A., Willemsen, R., Hermans, M. M. P., van den Ouweland, A. M. W., de Jong, J. G. N., Wevers, R. A., Renier, W. O., Schindler, D., Coll, M. J., Chabas, A., Sakuraba, H., Suzuki, Y., van Diggelen, O. P. Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype. J. Med. Genet. 33: 458-464, 1996. [PubMed: 8782044] [Full Text: https://doi.org/10.1136/jmg.33.6.458]
Kodama, K., Kobayashi, H., Abe, R., Ohkawara, A., Yoshii, N., Yotsumoto, S., Fukushige, T., Nagatsuka, Y., Hirabayashi, Y., Kanzaki, T. A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Meniere's syndrome and without mental retardation. Brit. J. Derm. 144: 363-368, 2001. [PubMed: 11251574] [Full Text: https://doi.org/10.1046/j.1365-2133.2001.04028.x]
van Diggelen, O. P., Schindler, D., Kleijer, W. J., Huijmans, J. G. M., Galjaard, H., Linden, H. U., Peter-Katalinic, J., Egge, H., Dabrowski, U., Cantz, M. Lysosomal alpha-N-acetylgalactosaminidase deficiency: a new inherited metabolic disease. (Letter) Lancet 330: 804 only, 1987. Note: Originally Volume II. [PubMed: 2889023] [Full Text: https://doi.org/10.1016/s0140-6736(87)92542-6]
van Diggelen, O. P., Schindler, D., Willemsen, R., Boer, M., Kleijer, W. J., Huijmans, J. G. M., Blom, W., Galjaard, H. Alpha-N-acetylgalactosaminidase deficiency, a new lysosomal storage disorder. J. Inherit. Metab. Dis. 11: 349-357, 1988. [PubMed: 3149698] [Full Text: https://doi.org/10.1007/BF01800424]
Wang, A. M., Bishop, D. F., Desnick, R. J. Human alpha-N-acetylgalactosaminidase-molecular cloning, nucleotide sequence, and expression of a full-length cDNA: homology with human alpha-galactosidase A suggests evolution from a common ancestral gene. J. Biol. Chem. 265: 21859-21866, 1990. [PubMed: 2174888]
Wang, A. M., Desnick, R. J. Structural organization and complete sequence of the human alpha-N-acetylgalactosaminidase gene: homology with the alpha-galactosidase A gene provides evidence for evolution from a common ancestral gene. Genomics 10: 133-142, 1991. [PubMed: 1646157] [Full Text: https://doi.org/10.1016/0888-7543(91)90493-x]
Wang, A. M., Ioannou, Y. A., Zeidner, K. M., Desnick, R. J. Murine alpha-N-acetylgalactosaminidase: isolation and expression of a full-length cDNA and genomic organization: further evidence of an alpha-galactosidase gene family. Molec. Genet. Metab. 65: 165-173, 1998. [PubMed: 9787108] [Full Text: https://doi.org/10.1006/mgme.1998.2750]
Wang, A. M., Kanzaki, T., Desnick, R. J. The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria. J. Clin. Invest. 94: 839-845, 1994. [PubMed: 8040340] [Full Text: https://doi.org/10.1172/JCI117404]
Wang, A. M., Schindler, D., Desnick, R. J. Schindler disease: the molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy. J. Clin. Invest. 86: 1752-1756, 1990. [PubMed: 2243144] [Full Text: https://doi.org/10.1172/JCI114901]
Wang, A. M., Schindler, D., Kanzaki, T., Desnick, R. J. Alpha-N-acetylgalactosaminidase gene: homology with human alpha-galactosidase A, and identification and confirmation of the mutations causing type I and II Schindler disease. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A169 only, 1990.
Wang, A. M., Stewart, C. L., Desnick, R. J. Schindler disease: generation of a murine model by targeted disruption of the alpha-N-acetylgalactosaminidase gene. (Abstract) Pediat. Res. 35: 115A only, 1994.
Yamauchi, T., Hiraiwa, M., Kobayashi, H., Uda, Y., Miyatake, T., Tsuji, S. Molecular cloning of two species of cDNAs for human alpha-N-acetylgalactosaminidase and expression in mammalian cells. Biochem. Biophys. Res. Commun. 170: 231-237, 1990. [PubMed: 2372288] [Full Text: https://doi.org/10.1016/0006-291x(90)91264-s]