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J Clin Invest. 1994 August; 94(2): 839–845.
PMCID: PMC296165

The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria.


Angiokeratoma corporis diffusum with glycopeptiduria is a recently recognized inborn error of glycoprotein catabolism resulting from the deficient activity of human alpha-N-acetylgalactosaminidase (E.C.; alpha-GalNAc). The first patient with this autosomal recessive disorder, a 46-yr-old consanguineous Japanese woman, presented with diffuse angiokeratoma, mild intellectual impairment, and peripheral neuroaxonal degeneration. Deficient alpha-GalNAc activity also has been reported in consanguineous brothers with an infantile-onset form of neuroaxonal dystrophy resulting from a missense mutation (designated E325K) in the alpha-GalNAc gene. To identify the mutation causing the phenotypically distinct adult-onset disorder, Southern and Northern hybridization analyses of DNA and RNA from the affected homozygote were performed which revealed a grossly normal alpha-GalNAc gene structure and normal transcript size and abundancy. Reverse transcription, amplification, and sequencing of the alpha-GalNAc transcript identified a single C to T transition at nucleotide (nt) 985 that predicted an arginine to tryptophan substitution in residue 329 (designated R329W) of the alpha-GalNAc polypeptide. This base substitution was confirmed by hybridization of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Transient expression of an alpha-GalNAc construct containing the R329W mutation resulted in the expression of an immunoreactive polypeptide which had no detectable alpha-GalNAc activity. Comparison of the biosynthesis and stabilities of the transiently expressed and radiolabeled normal, E325K (infantile-onset) and R329W (adult-onset) alpha-GalNAc polypeptides in COS-1 cells indicated that both the mutant 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.

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  • Kanzaki T, Yokota M, Mizuno N, Matsumoto Y, Hirabayashi Y. Novel lysosomal glycoaminoacid storage disease with angiokeratoma corporis diffusum. Lancet. 1989 Apr 22;1(8643):875–877. [PubMed]
  • Kanzaki T, Wang AM, Desnick RJ. Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria. J Clin Invest. 1991 Aug;88(2):707–711. [PMC free article] [PubMed]
  • Kanzaki T, Yokota M, Irie F, Hirabayashi Y, Wang AM, Desnick RJ. Angiokeratoma corporis diffusum with glycopeptiduria due to deficient lysosomal alpha-N-acetylgalactosaminidase activity. Clinical, morphologic, and biochemical studies. Arch Dermatol. 1993 Apr;129(4):460–465. [PubMed]
  • van Diggelen OP, Schindler D, Kleijer WJ, Huijmans JM, Galjaard H, Linden HU, Peter-Katalinic J, Egge H, Dabrowski U, Cantz M. Lysosomal alpha-N-acetylgalactosaminidase deficiency: a new inherited metabolic disease. Lancet. 1987 Oct 3;2(8562):804–804. [PubMed]
  • van Diggelen OP, Schindler D, Willemsen R, Boer M, Kleijer WJ, Huijmans JG, Blom W, Galjaard H. alpha-N-acetylgalactosaminidase deficiency, a new lysosomal storage disorder. J Inherit Metab Dis. 1988;11(4):349–357. [PubMed]
  • Schindler D, Bishop DF, Wolfe DE, Wang AM, Egge H, Lemieux RU, Desnick RJ. Neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency. N Engl J Med. 1989 Jun 29;320(26):1735–1740. [PubMed]
  • Linden HU, Klein RA, Egge H, Peter-Katalinic J, Dabrowski J, Schindler D. Isolation and structural characterization of sialic-acid-containing glycopeptides of the O-glycosidic type from the urine of two patients with an hereditary deficiency in alpha-N-acetylgalactosaminidase activity. Biol Chem Hoppe Seyler. 1989 Jul;370(7):661–672. [PubMed]
  • Hirabayashi Y, Matsumoto Y, Matsumoto M, Toida T, Iida N, Matsubara T, Kanzaki T, Yokota M, Ishizuka I. Isolation and characterization of major urinary amino acid O-glycosides and a dipeptide O-glycoside from a new lysosomal storage disorder (Kanzaki disease). Excessive excretion of serine- and threonine-linked glycan in the patient urine. J Biol Chem. 1990 Jan 25;265(3):1693–1701. [PubMed]
  • Schindler D, Kanzaki T, Desnick RJ. A method for the rapid detection of urinary glycopeptides in alpha-N-acetylgalactosaminidase deficiency and other lysosomal storage diseases. Clin Chim Acta. 1990 Sep;190(1-2):81–91. [PubMed]
  • Wang AM, Bishop DF, Desnick RJ. 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. 1990 Dec 15;265(35):21859–21866. [PubMed]
  • Wang AM, Desnick RJ. 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. 1991 May;10(1):133–142. [PubMed]
  • Sweeley CC, Ledonne NC, Jr, Robbins PW. Post-translational processing reactions involved in the biosynthesis of lysosomal alpha-N-acetylgalactosaminidase in cultured human fibroblasts. Arch Biochem Biophys. 1983 May;223(1):158–165. [PubMed]
  • Wang AM, Schindler D, Desnick R. Schindler disease: the molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy. J Clin Invest. 1990 Nov;86(5):1752–1756. [PMC free article] [PubMed]
  • Hu P, Reuser AJ, Janse HC, Kleijer WJ, Schindler D, Sakuraba H, Tsuji A, Suzuki Y, van Diggelen OP. Biosynthesis of human alpha-N-acetylgalactosaminidase: defective phosphorylation and maturation in infantile alpha-NAGA deficiency. Biochem Biophys Res Commun. 1991 Mar 29;175(3):1097–1103. [PubMed]
  • Bernstein HS, Bishop DF, Astrin KH, Kornreich R, Eng CM, Sakuraba H, Desnick RJ. Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene. J Clin Invest. 1989 Apr;83(4):1390–1399. [PMC free article] [PubMed]
  • Bishop DF, Desnick RJ. Affinity purification of alpha-galactosidase A from human spleen, placenta, and plasma with elimination of pyrogen contamination. Properties of the purified splenic enzyme compared to other forms. J Biol Chem. 1981 Feb 10;256(3):1307–1316. [PubMed]
  • Aldridge J, Kunkel L, Bruns G, Tantravahi U, Lalande M, Brewster T, Moreau E, Wilson M, Bromley W, Roderick T, et al. A strategy to reveal high-frequency RFLPs along the human X chromosome. Am J Hum Genet. 1984 May;36(3):546–564. [PubMed]
  • Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Lehrach H, Diamond D, Wozney JM, Boedtker H. RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochemistry. 1977 Oct 18;16(21):4743–4751. [PubMed]
  • Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. [PubMed]
  • Messing J, Vieira J. A new pair of M13 vectors for selecting either DNA strand of double-digest restriction fragments. Gene. 1982 Oct;19(3):269–276. [PubMed]
  • Sanger F, Coulson AR, Barrell BG, Smith AJ, Roe BA. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. [PubMed]
  • Theophilus B, Latham T, Grabowski GA, Smith FI. Gaucher disease: molecular heterogeneity and phenotype-genotype correlations. Am J Hum Genet. 1989 Aug;45(2):212–225. [PubMed]
  • Chou PY, Fasman GD. Prediction of the secondary structure of proteins from their amino acid sequence. Adv Enzymol Relat Areas Mol Biol. 1978;47:45–148. [PubMed]
  • Garnier J, Osguthorpe DJ, Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol. 1978 Mar 25;120(1):97–120. [PubMed]
  • Wolf H, Modrow S, Motz M, Jameson BA, Hermann G, Förtsch B. An integrated family of amino acid sequence analysis programs. Comput Appl Biosci. 1988 Mar;4(1):187–191. [PubMed]
  • Wong GG, Witek JS, Temple PA, Wilkens KM, Leary AC, Luxenberg DP, Jones SS, Brown EL, Kay RM, Orr EC, et al. Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. Science. 1985 May 17;228(4701):810–815. [PubMed]
  • Chen C, Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. [PMC free article] [PubMed]
  • Schägger H, von Jagow G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem. 1987 Nov 1;166(2):368–379. [PubMed]
  • Tarentino AL, Trimble RB, Plummer TH., Jr Enzymatic approaches for studying the structure, synthesis, and processing of glycoproteins. Methods Cell Biol. 1989;32:111–139. [PubMed]
  • Desnick RJ. Gaucher disease: a century of delineation and understanding. Prog Clin Biol Res. 1982;95:1–30. [PubMed]
  • Takahashi T, Suchi M, Desnick RJ, Takada G, Schuchman EH. Identification and expression of five mutations in the human acid sphingomyelinase gene causing types A and B Niemann-Pick disease. Molecular evidence for genetic heterogeneity in the neuronopathic and non-neuronopathic forms. J Biol Chem. 1992 Jun 25;267(18):12552–12558. [PubMed]
  • Myerowitz R. Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3955–3959. [PubMed]
  • Myerowitz R, Costigan FC. The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase. J Biol Chem. 1988 Dec 15;263(35):18587–18589. [PubMed]
  • Navon R, Proia RL. The mutations in Ashkenazi Jews with adult GM2 gangliosidosis, the adult form of Tay-Sachs disease. Science. 1989 Mar 17;243(4897):1471–1474. [PubMed]

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