Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes.

BACKGROUND: Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A (alpha-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 alpha-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 alpha-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, I9IT and F113L, respectively. In 38 classically affected patients, 33 new mutations were identified including 20 missense (MIT, 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.

Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the alpha-galactosidase A gene.

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A gene 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 in Fabry families, the alpha-galactosidase A coding and flanking intronic sequences from 23 unrelated Fabry hemizygotes were analyzed. In patients with the classic phenotype, 16 new missense and nonsense mutations and four small exonic gene rearrangements were identified: C52S, C56F, E59K, L89R, R100K, R112H, L131P, A143P, G144V, C172Y, D244N, N272K, A288D, W81X, Q99X, Q157X, R301X, 25del1, 333del18, 358del6, and 1020del1. The R112H mutation at a CpG dinucleotide resulted in residual activity and a mild variant phenotype while the R112C lesion caused the classic disease manifestations, defining a genotype/phenotype correlation for sense and antisense mutations at the same CpG dinucleotide. In addition, two complex rearrangements, each involving two mutational events, occurred in classic hemizygotes. Both rearrangements resulted in missense mutations that did not change the reading frame. Notably, three of the deletions occurred within 11 codons in exon 2, thereby defining a 'hot-spot' for deletions. These studies revealed that most mutations in the alpha-galactosidase A gene causing Fabry disease were private, that codons 111-122 defined a deletion hot-spot, and that different substitutions of the same codon resulted in markedly different disease phenotypes.