Skip to main content
SpringerLink
Log in

Fabry Disease: Thirty-Five Mutations in the α-Galactosidase A Gene in Patients with Classic and Variant Phenotypes

  • Original Articles
  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

Background

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the α-galactosidase A (α-Gal A) gene located at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes and for precise carrier detection, the α-Gal A lesions in 42 unrelated Fabry hemizygotes were determined.

Materials and Methods

Genomic DNA was isolated from affected probands and their family members. The seven α-galactosidase A exons and flanking intronic sequences were PCR amplified and the nucleotide sequence was determined by solid-phase direct sequencing.

Results

Two patients with the mild cardiac phenotype had missense mutations, I91T and F113L, respectively. In 38 classically affected patients, 33 new mutations were identified including 20 missense (M1T, A31V, H46R, Y86C, L89P, D92Y, C94Y, A97V, R100T, Y134S, G138R, A143T, S148R, G163V, D170V, C202Y, Y216D, N263S, W287C, and N298S), two nonsense (Q386X, W399X), one splice site mutation (IVS4 + 2T → C), and eight small exonic insertions or deletions (304del1, 613del9, 777del1, 1057del2, 1074del2, 1077del1, 1212del3, and 1094ins1), which identified exon 7 as a region prone to gene rearrangements. In addition, two unique complex rearrangements consisting of contiguous small insertions and deletions were found in exons 1 and 2 causing L45R/H46S and L120X, respectively.

Conclusions

These studies further define the heterogeneity of mutations causing Fabry disease, permit precise carrier identification and prenatal diagnosis in these families, and facilitate the identification of candidates for enzyme replacement therapy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Desnick RJ, Ioannou YA, Eng CM. (1995) α-Galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The Metabolic and Molecular Bases of Inherited Disease, 7th ed. McGraw-Hill, New York, pp. 2741–2784.

    Google Scholar 

  2. Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, Yoshida A, Kuriyama M, Hayashibe H, Sakuraba H, et al. (1995) An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N. Engl. J. Med. 333: 288–293.

    Article  CAS  PubMed  Google Scholar 

  3. 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. U.S.A. 83: 4859–4863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bishop DF, Kornreich R, Eng CM, 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. Plenum, New York, pp. 809–822.

    Chapter  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Hostikka SL, Eddy RL, Byers MG, Hoyhtya M, Shows TB, Tryggvason K. (1990) Identification of a distinct type IV collagen α-chain with restricted kidney distribution and assignment of its gene to the locus of X-linked Alport syndrome. Proc. Natl. Acad. Sci. U.S.A. 87: 1606–1610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, Gregory MC, Skolnick MH, Atkin CL, Tryggvason K. (1990) Identification of mutations in the COL4A5 gene in Alport syndrome. Science 248: 1224–1227.

    Article  CAS  PubMed  Google Scholar 

  9. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, Hammarström L, Kinnon C, Levinsky R, Bobrow M, Smith CIE, Bentley DR. (1993) The gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. Nature 361: 226–233.

    Article  CAS  PubMed  Google Scholar 

  10. Caggana M, Ashley GA, Desnick RJ, Eng CM. (1997) Fabry disease: Molecular carrier detection and prenatal diagnosis by analysis of closely linked polymorphisms at xq22.1. Am. J. Med. Genet. (in press).

  11. Eng CM, Desnick RJ. (1994) Molecular basis of Fabry disease: Mutations and polymorphisms in the human α-galactosidase A gene. Hum. Mutat. 3: 103–111.

    Article  CAS  PubMed  Google Scholar 

  12. von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hübner G, Olsen EGJ, Christomanou H, Kandolf R, Bishop DF, Desnick RJ. (1991) An atypical variant of Fabry’s disease confined to manifestations of the heart. N. Engl. J. Med. 324: 395–399.

    Article  Google Scholar 

  13. Sakuraba H, Oshima A, Fukuhara Y, et al. (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.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Eng CM, Niehaus DJ, Enriquez A, Burgert TS, Ludman MD, Desnick RJ. (1994) Fabry disease: Twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the α-galactosidase A gene. Hum. Molec. Genet. 3: 1795–1799.

    Article  CAS  PubMed  Google Scholar 

  15. Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ. (1993) Nature and frequency of mutations in the α-galactosidase A gene causing Fabry disease. Am. J. Hum. Genet. 53: 1186–1197.

    PubMed  PubMed Central  CAS  Google Scholar 

  16. Desnick RJ, Allen KY, Desnick SJ, Raman MK, Bernlohr RW, Krivit W. (1973) Fabry disease: Enzymatic diagnosis of hemizygotes and heterozygotes: α-Galactosidase activities in plasma, serum, urine and leukocytes. J. Lab. Clin. Med. 81: 157–171.

    PubMed  CAS  Google Scholar 

  17. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sambrook J, Fritsch EF, Maniatis T. (1989). Molecular Cloning: A Laboratory Manual, 2nd ed. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.

    Google Scholar 

  19. Kornreich R, Desnick RJ. (1993) Fabry disease: Detection of gene rearrangements in the human α-galactosidase A gene by multiplex PCR amplification. Hum. Mutat. 2: 108–111.

    Article  CAS  PubMed  Google Scholar 

  20. Cooper DN, Youssoufian H. (1988) The CpG dinucleotide and human genetic disease. Hum. Genet. 78: 151–155.

    Article  CAS  PubMed  Google Scholar 

  21. Wang AM, Bishop DF, Desnick RJ. (1990) Human α-N-acetylgalactosaminidase: Molecular cloning, nucleotide sequence, and expression of full length cDNA. Homology with human α-Gal A suggests evolution from a common ancestral gene. J. Biol. Chem. 265: 21859–21866.

    PubMed  CAS  Google Scholar 

  22. Zeidner KM, Ioannou YA, Desnick, RJ. (1993) Human α-Gal A active site residue: Determination by homology, mutagenesis, and transient expression. Am. J. Hum. Genet. 53: 1682A.

    Google Scholar 

  23. Yamakawa-Kobayashi K, Kobayashi T, Yanagi H, Shimakura Y, Satoh J, Hamaguchi H. (1994) A novel complex mutation in the LDL receptor gene probably caused by the simultaneous occurrence of deletion and insertion in the same region. Hum. Genet. 93: 625–628.

    Article  CAS  PubMed  Google Scholar 

  24. Gibbs RA, Nguyen P-N, McBride LJ, Koepf SM, Caskey CT. (1989) Identification of mutations leading to the Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA. Proc. Natl. Acad. Sci. U.S.A. 86: 1919–1923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nogueira CP, McGuire MC, Graeser C, Bartels CF, Arpagaus M, Van der Spek AFL, Lightstone H, Lockridge O, La Du BN. (1990) Identification of a frameshift mutation responsible for the silent phenotype of human serum cholinesterase, Gly 117 (GGT → GGAG). Am. J. Hum. Genet. 46: 934–942.

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Pease LR, Horton RM, Pullen JK, Yun TJ. (1993) Unusual mutation clusters provide insight into class I gene conversion mechanisms. Mol. Cell Biol. 13: 4374–4381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cooper DN, Krawczak M. (1991) Mechanisms of insertional mutagenesis in human genes causing genetic disease. Hum. Genet. 87: 409–415.

    PubMed  CAS  Google Scholar 

  28. Davies JP, Eng CM, Hill JA, Malcolm S, MacDermot S, Winchester B, Desnick RJ. (1996) Fabry disease: 14 α-galactosidase A mutations in unrelated families from the United Kingdom and Europe. Eur. J. Hum. Genet. 4: 219–224.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Sheri Mural for assistance in DNA sequencing. We also thank the following physicians for referral of patients and/or diagnostic specimens: Drs. G. Wilson, M. Iamethi, P. Aula, E. K. M. Smith, C. Harris, N. Doyle, L. Clarke, A. Bottani, L. Workman, I. R. C. Sparrow, K. MacDermott, G. Hogansson, P. Slee, B. Kramer, G. Grabowski, J. Graf, B. Wolf, A. Skarbonk, and L. Emtestam. This work was supported in part by grants from the National Institutes of Health including a Merit Award (R37 DK34045), a grant (MO1 RR00071) for the Mount Sinai General Clinical Research Center from the National Center of Research Resources, a grant (P30 HD28822) for the Mount Sinai Child Health Research Center, and a grant from the American Heart Association (New York City affiliate).

Author information

Authors and Affiliations

  1. Department of Human Genetics, Mount Sinai School of Medicine, New York, NY, USA

    Christine M. Eng, Grace A. Ashley, Tania S. Burgert, Annette L. Enriquez, Marcus D’Souza & Robert J. Desnick

  2. Department of Pediatrics, Mount Sinai School of Medicine, New York, New York, USA

    Christine M. Eng & Robert J. Desnick

  3. Department of Human Genetics, Box 1498, One Gustave Levy Place, New York, NY, 10029, USA

    Christine M. Eng

Authors
  1. Christine M. Eng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Grace A. Ashley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tania S. Burgert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Annette L. Enriquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marcus D’Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert J. Desnick
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Beutler
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eng, C.M., Ashley, G.A., Burgert, T.S. et al. Fabry Disease: Thirty-Five Mutations in the α-Galactosidase A Gene in Patients with Classic and Variant Phenotypes. Mol Med 3, 174–182 (1997). https://doi.org/10.1007/BF03401671

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03401671

Keywords

Search

Navigation