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Research Article Free access | 10.1172/JCI114027

Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.

H S Bernstein, D F Bishop, K H Astrin, R Kornreich, C M Eng, H Sakuraba, and R J Desnick

Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York 10029.

Find articles by Bernstein, H. in: PubMed | Google Scholar

Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York 10029.

Find articles by Bishop, D. in: PubMed | Google Scholar

Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York 10029.

Find articles by Astrin, K. in: PubMed | Google Scholar

Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York 10029.

Find articles by Kornreich, R. in: PubMed | Google Scholar

Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York 10029.

Find articles by Eng, C. in: PubMed | Google Scholar

Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York 10029.

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Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, New York 10029.

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Published April 1, 1989 - More info

Published in Volume 83, Issue 4 on April 1, 1989
J Clin Invest. 1989;83(4):1390–1399. https://doi.org/10.1172/JCI114027.
© 1989 The American Society for Clinical Investigation
Published April 1, 1989 - Version history
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Abstract

Fabry disease, an X-linked recessive disorder of glycosphingolipid catabolism, results from the deficient activity of the lysosomal hydrolase, alpha-galactosidase. Southern hybridization analysis of the alpha-galactosidase gene in affected hemizygous males from 130 unrelated families with Fabry disease revealed six with different gene rearrangements and one with an exonic point mutation resulting in the obliteration of an Msp I restriction site. Five partial gene deletions were detected ranging in size from 0.4 to greater than 5.5 kb. Four of these deletions had breakpoints in intron 2, a region in the gene containing multiple Alu repeat sequences. A sixth genomic rearrangement was identified in which a region of about 8 kb, containing exons 2 through 6, was duplicated by a homologous, but unequal crossover event. The Msp I site obliteration, which mapped to exon 7, was detected in an affected hemizygote who had residual enzyme activity. Genomic amplification by the polymerase chain reaction and sequencing revealed that the obliteration resulted from a C to T transition at nucleotide 1066 in the coding sequence. This point mutation, the first identified in Fabry disease, resulted in an arginine356 to tryptophan356 substitution which altered the enzyme's kinetic and stability properties. The detection of these abnormalities provided for the precise identification of Fabry heterozygotes, thereby permitting molecular pedigree analysis in these families which revealed paternity exclusions and the first documented new mutations in this disease.

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