PMID- 10208848
OWN - NLM
STAT- MEDLINE
DCOM- 19990601
LR  - 20171116
IS  - 0006-291X (Print)
IS  - 0006-291X (Linking)
VI  - 257
IP  - 3
DP  - 1999 Apr 21
TI  - Fabry disease: identification of novel alpha-galactosidase A mutations and
      molecular carrier detection by use of fluorescent chemical cleavage of
      mismatches.
PG  - 708-13
AB  - Fabry disease (FD) (angiokeratoma corporis diffusum) is an X-linked inborn error 
      of glycosphingolipid metabolism caused by defects in the lysosomal
      alpha-galactosidase A gene (GLA). The enzymatic defect leads to the systemic
      accumulation of neutral glycosphingolipids with terminal alpha-galactosyl
      moieties. Clinically, affected hemizygous males have angiokeratoma, severe
      acroparesthesia, renal failure, and vasculopathy of the heart and brain. While
      demonstration of alpha-galactosidase deficiency in leukocytes is diagnostic in
      affected males, enzymatic detection of female carriers is often inconclusive, due
      to random X-chromosomal inactivation, underlining the need of molecular
      investigations for accurate genetic counseling. By use of chemical cleavage of
      mismatches adapted to fluorescence-based detection systems, we have characterized
      the mutations underlying alpha-Gal A deficiency in 16 individuals from six
      unrelated families with FD. The mutational spectrum included five missense
      mutations (C202W, C223G, N224D, R301Q, and Q327K) and one splice-site mutation
      [IVS3 G(-1) --> C]. Studies at the mRNA level showed that the latter led to
      altered pre-mRNA splicing with consequent alteration of the mRNA translational
      reading frame and generation of a premature termination codon of translation. By 
      use of this strategy, carrier status was accurately assessed in all seven at-risk
      females tested, whereas enzymatic dosages failed to diagnose or exclude
      heterozygosity.
CI  - Copyright 1999 Academic Press.
FAU - Germain, D P
AU  - Germain DP
AD  - CHU Cochin Port-Royal, Universite Rene Descartes, Paris, France.
      dominique.germain@brs.ap-hop-paris.fr
FAU - Poenaru, L
AU  - Poenaru L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Codon, Terminator)
RN  - 0 (Fluorescent Dyes)
RN  - 9007-49-2 (DNA)
RN  - EC 3.2.1.22 (alpha-Galactosidase)
SB  - IM
MH  - Adult
MH  - Amino Acid Sequence
MH  - Base Pair Mismatch/*genetics
MH  - Base Sequence
MH  - Codon, Terminator/genetics
MH  - DNA/genetics/*metabolism
MH  - DNA Mutational Analysis
MH  - Dosage Compensation, Genetic
MH  - Exons/genetics
MH  - Fabry Disease/blood/diagnosis/*genetics
MH  - Female
MH  - Fluorescent Dyes
MH  - Genetic Carrier Screening/*methods
MH  - Humans
MH  - Male
MH  - Molecular Sequence Data
MH  - *Mutation
MH  - Mutation, Missense/genetics
MH  - Pedigree
MH  - RNA Splicing/genetics
MH  - Sensitivity and Specificity
MH  - alpha-Galactosidase/blood/chemistry/*genetics
EDAT- 1999/04/20 00:00
MHDA- 1999/04/20 00:01
CRDT- 1999/04/20 00:00
PHST- 1999/04/20 00:00 [pubmed]
PHST- 1999/04/20 00:01 [medline]
PHST- 1999/04/20 00:00 [entrez]
AID - S0006-291X(99)90310-8 [pii]
AID - 10.1006/bbrc.1999.0310 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 1999 Apr 21;257(3):708-13. doi:
      10.1006/bbrc.1999.0310.