Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Point mutations in the upstream region of the α-galactosidase A gene exon 6 in an atypical variant of Fabry disease


Single point mutations in the upstream region of exon 6 of the α-galactosidase A gene were found in two Japanese cases of the cardiac form of Fabry disease; 301Arg→Gln (902G→A) in a case that has already been published and 279Gln→Glu (835C→G) in a new case. They both expressed markedly low, but significant, amounts of residual activity in COS-1 cells. In contrast, two unrelated cases with classic Fabry disease were found to have different point mutations, which showed a complete loss of enzyme activity in a transient expression assay; 328Gly→Arg (982G→A) in the downstream region of exon 6 in one case and two combined mutations, 66Glu→Gln (196G→C)/112Arg→Cys (334C→T), in exon 2 in the other. We conclude, on the basis of the results recorded in this study and those in previous reports, that the pathogenesis of atypical Fabry disease is closely associated with point mutations in the upstream region of exon 6 of the α-galactosidase A gene.

This is a preview of subscription content, log in to check access.


  1. Bach G, Rosenmann E, Karana A, Cohen T (1982) Pseudodeficiency of α-galactosidase A. Clin Genet 21:59–64

  2. 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-galactosidase gene. J Clin Invest 83:1390–1399

  3. Bishop DF, Grabowski GA, Desnick RJ (1981) Fabry disease: an asymptomatic hemizygote with significant residual α-galactosidase A activity. Am J Hum Genet 33:71A

  4. Bishop DF, Kornreich R, Desnick RJ (1988) Structural organization of the human α-galactosidase A gene: further evidence for the absence of a 3′ untranslated region. Proc Natl Acad Sci USA 85:3903–3907

  5. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

  6. Chou PY, Fasman GD (1978) Prediction of the secondary structure of proteins from their amino-acid sequence. Adv Enzymol 47:45–148

  7. Clarke JTR, Knaack J, Crawhall JC, Wolfe LS (1971) Ceramide trihexosidosis (Fabry's disease) without skin lesions. N Engl J Med 284:233–235

  8. 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 1751–1796

  9. Fukuhara Y, Sakuraba H, Oshima A, Shimmoto M, Nagao Y, Nadaoka Y, Suzuki T, Suzuki Y (1990) Small deletion formation of human α-galactosidase A gene in Fabry disease: direct repeat sequence as a possible cause of slipped mispairing. Biochem Biophys Res Commun 170:296–300

  10. Ishii S, Sakuraba H, Shimmoto M, Minamikawa-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

  11. Kobayashi T, Kira J, Shinnoh N, Goto I, Kuroiwa Y (1985) Fabry's disease with partially deficient hydrolysis of ceramide trihexoside. J Neurol Sci 67:179–185

  12. 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 α-galactosidase A activity caused by a single amino-acid substitution of Pro-40 by Ser. FEBS Lett 259:353–356

  13. Kornreich R, Desnick RJ, Bishop DF (1989) Nucleotide sequence of the human α-galactosidase A gene. Nucleic Acids Res 17:3301–3302

  14. Kornreich R, Bishop DF, Desnick RJ (1990) α-Galactosidase A gene rearrangement causing Fabry disease: identification of short direct repeats at break-points in an Alu-rich gene. J Biol Chem 265:9319–9326

  15. Mayes JS, Scheere JB, Sifers RN, Donaldson ML (1981) Differential assay for lysosomal α-galactosidase in human tissue and its application to Fabry's disease. Clin Chim Acta 112:247–251

  16. 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

  17. Romeo G, D'Urso M, Pisacane A, Blum E, De Falco A, Ruffilli A (1975) Residual activity of α-galactosidase A in Fabry's disease. Biochem Genet 13:615–628

  18. Sakuraba H (1989) Molecular genetics of Fabry disease. Seikagaku (Tokyo) 61:294–299

  19. 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 diesease. Am J Hum Genet 47:784–789

  20. Scheidt WV, Eng CM, Fitzmaurice TF, Erdmann E, Hubner G, Olsen EGJ, Christomanou H, Kandolf R, Bishop DF, Desnick RJ (1991) An atpyical variant of Fabry's disease with manifestations confined to the myocardium. N Engl J Med 324:395–399

  21. Yamamoto K, Tanouchi J, Kagiya T, Iwai K, Fujii K, Ozaki H, Matsuyama T, Mishima M, Hori M (1989) A case of Fabry's disease manifested only with myocardial lesion. Shinzo (Tokyo) 3:326–330

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ishii, S., Sakuraba, H. & Suzuki, Y. 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 (1992). https://doi.org/10.1007/BF00207037

Download citation


  • Enzyme Activity
  • Metabolic Disease
  • Point Mutation
  • Single Point
  • Upstream Region