title: Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Eng
authors.forename: G A
authors.initials: GA
authors.lastname: Ashley
authors.forename: T S
authors.initials: TS
authors.lastname: Burgert
authors.forename: A L
authors.initials: AL
authors.lastname: Enriquez
authors.forename: M
authors.initials: M
authors.lastname: D'Souza
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005091:Exons; D000795:Fabry Disease / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D000519:alpha-Galactosidase