Abstract
Five point mutations were identified in unrelated Japanese Fabry disease hemizygotes: three new missense mutations, C142Y (425 G → A), A156V (467 C → T), and L166V (496 C → G) in exon 3; one new splice site mutation at the 3′ end of the consensus sequence in exon 4; one previously reported nonsense mutation, W44X (131 G → A). C142Y expressed 50% of the normal enzyme protein in COS-1 cells, but catalytic activity was not detected. Both A156V and L166V expressed significant amounts of residual enzyme activity (6.7% and 9.8%) and enzyme proteins (10% each), the latter were more thermolabile at neutral pH than at acid pH, in vitro.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Aldridge J, Kunkel L, Bruns G, Tantravahi U, Lalande M, Brewster T, Moreau E, Wilson M, Bromley W, Roderick T, Latt SA (1984) A strategy to reveal high frequency RFLPs along the human X chromosome. Am J Hum Genet 36:546–564
Bernstein HS, Bishop DF, Astrin KH, Kornreich R, Eng CM, Sakuraba H, Desnick RJ (1989) Fabry disease: six gene rearrangements and an exonic point mutation in the α-galactosi dase gene. J Clin Invest 83:1390–1399
Bishop DF, Calhoun DH, Bernstein HS, Hantzopoulos P, Quinn M, Desnick RJ (1986) Human α-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc Natl Acad Sci USA 83:4859–4863
Bishop DF, Kornreich R, Eng CE, Ioannou YA, Fitzmaurice TF, Desnick RJ (1988) Human α-galactosidase: characterization and eukaryotic expression of the full-length cDNA and structural organization of the gene. In: Salvayre R, Douste-Blazy L, Gatt S (eds) Lipid storage disorders: biological and medical aspects. Plenum, New York, pp 809–822
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Calhoun DH, Bishop DF, Bernstein HS, Quinn M, Hantzopoulos P, Desnick RJ (1985) Fabry disease: isolation of a cDNA clone encoding human α-galactosidase A. Proc Natl Acad Sci USA 82:7364–7368
Desnick RJ, Bishop DF (1989) Fabry disease: α-galactosidase deficiency and Schindler disease: α-N-acetylgalactosaminidase deficiency. In: Scriver CR, Beaudet AI, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGrawHill, New York, pp 1751–1780
Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ (1993) Nature and frequency of mutations in the α-galactosidase A gene that cause Fabry disease. Am J Hum Genet 53:1186–1197
Fukuhara Y, Sakuraba H, Oshima A, Shimmoto M, Nagao Y, Nadaoka Y, Suzuki T, Suzuki Y (1990) Partial deletion of human α-galactosidase A gene in Fabry disease: direct repeat sequences as a possible cause of slipped mispairing. Biochem Biophys Res Commun 170:296–300
Ishii S, Sakuraba H, Shimmoto M, Tachino R, Suzuki T, Suzuki Y (1991) Fabry disease: detection of 13-bp deletion in α-galactosidase A gene and its application to gene diagnosis of heterozygotes. Ann Neurol 29:560–564
Ishii S, Sakuraba H, Suzuki Y (1992) Point mutations in the upstream region of the α-galactosidase A gene exon 6 in an atypical variant of Fabry disease. Hum Genet 89:29–32
Ishii S, Kase R, Sakuraba H, Suzuki Y (1993) Characterization of a mutant α-galactosidase gene product for the late-onset cardiac form of Fabry disease. Biochem Biophys Res Commun 197:1585–1589
Ishii S, Kase R, Sakuraba H, Fujita S, Sugimoto M, Tomita K, Semba T, Suzuki Y (1994) Human α-galactosidase gene expression: significance of two peptide regions encoded by exon 1–2 and 6. Biochim Biophys Acta 1204:265–270
Kornreich R, Bishop DF, Desnick RJ (1989) Nucleotide sequence of the human αgalactosidase A gene. Nucleic Acids Res 17:3301–3302
Koide T, Ishiura M, Iwai K, Inoue M, Kaneda Y, Okada Y, Uchida T (1990) A case of Fabry's disease in a patient with no αgalactosidase A activity caused by a single amino-acid substitution of Pro-40 by Ser. FEBS Lett 259:353–356
Minamikawa-Tachino R, Ishii K, Sakuraba H, Suzuki Y, Kaminuma T (1993) Quantitative analysis of dystrophin gene amplification products using PC-based image analysis system. Int J Biomed Comput 33:277–286
Nagao Y, Nakashima H, Fukuhara Y, Shimmoto M, Oshima A, Sakuraba H, Ikari Y, Mori Y, Suzuki Y (1991) Hypertrophic cardiomyopathy in late-onset variant of Fabry disease with high residual activity of α-galactosidase A. Clin Genet 39:233–237
Sakuraba H, Oshima A, Fukuhara Y, Shimmoto M, Nagao Y, Bishop DF, Desnick RJ, Suzuki Y (1990) Identification of point mutations in the α-galactosidase A gene in classical and atypical hemizygotes with Fabry disease. Am J Hum Genet 47:784–789
Sakuraba H, Eng CM, Desnick RJ, Bishop DF (1992) Invariant exon skipping in the human α-galactosidase A pre-mRNA: A g+1 to t substitution in a 5′-splice site causing Fabry disease. Genomics 12:643–650
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
Scheidt WV, Eng CM, Fitzmaurice TF, Erdmann E, Hubner G, Olsen EGL, Christomanou H, Kandolf R, Bishop DF, Desnick RJ (1991) An atypical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 324:395–399
Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354
Yokoi T, Shinoda K, Ohno I, Kato K, Miyawaki T, Taniguchi N (1991) A 3′ splice site consensus sequence mutation in the intron 3 of the α-galactosidase A gene in a patient with Fabry disease. Jpn J Hum Genet 36:245–250
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Okumiya, T., Ishii, S., Kase, R. et al. α-Galactosidase gene mutations in Fabry disease: heterogeneous expressions of mutant enzyme proteins. Hum Genet 95, 557–561 (1995). https://doi.org/10.1007/BF00223869
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00223869