Twenty novel mutations in the alpha-galactosidase A gene causing Fabry disease.
BACKGROUND
Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A). The nature of the molecular lesions in the alpha-Gal A gene in 30 unrelated families was determined to provide precise heterozygote detection, prenatal diagnosis, and define genotype-phenotype correlations.


METHODS
Genomic DNA was isolated from affected males and/or carrier females from 30 unrelated families with Fabry disease. The entire alpha-Gal A coding region and flanking intronic sequences were analyzed by PCR amplification and automated sequencing.


RESULTS
Twenty new mutations were identified, each in a single family: C142R, G183D, S235C, W236L, D244H, P259L, M267I, I289F, Q321E, C378Y, C52X, W277X, IVS4(+4), IVS6(+2), IVS6(-1), 35del13, 256del1, 892ins1, 1176del4, and 1188del1. In the remaining 10 unrelated Fabry families, 9 previously reported mutations were detected: M42V, R112C, S148R, D165V, N215S (in 2 families), Q99X, C142X, R227X, and 1072del3. Haplotype analysis using markers closely flanking the alpha-Gal A gene indicated that the two patients with the N215S lesion were unrelated. The IVS4(+4) mutation was a rare intronic splice site mutation that causes Fabry disease.


CONCLUSIONS
These studies further define the heterogeneity of mutations in the alpha-Gal A gene causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis, and help delineate phenotype-genotype correlations in this disease. </AB
Topaloglu
A K
AK
Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Ashley
G A
GA
Tong
B
B
Shabbeer
J
J
Astrin
K H
KH
Eng
C M
CM
Desnick
R J
RJ
D017398:Alternative Splicing / Q000235:genetics; D002874:Chromosome Mapping; D005091:Exons / Q000235:genetics; D000795:Fabry Disease / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D005819:Genetic Markers; D006801:Humans; D007438:Introns / Q000235:genetics; D008052:Lipid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D014960:X Chromosome / Q000235:genetics; D000519:alpha-Galactosidase / Q000235:genetics*
D005819:Genetic Markers; D000519:alpha-Galactosidase