PMID- 10477432
OWN - NLM
STAT- MEDLINE
DCOM- 19991012
LR  - 20061115
IS  - 1059-7794 (Print)
IS  - 1059-7794 (Linking)
VI  - 14
IP  - 3
DP  - 1999
TI  - Identification of 12 novel mutations and two new polymorphisms in the
      arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in
      Spanish metachromatic leukodystrophy patients.
PG  - 240-8
AB  - Arylsulfatase A (ARSA) deficiency is the main cause of metachromatic
      leukodystrophy (MLD), a lysosomal disorder with no specific treatment. In view of
      the importance of genetic counseling, analyses of mutations and polymorphisms,
      including the ARSA pseudodeficiency allele, were carried out in 18 unrelated
      Spanish MLD patients. A systematic search allowed us to identify 100% of the
      alleles involving 17 different mutations, 12 of which are novel: G32S, L68P,
      R84W, P94A, G99V, P136S, W193X, H227Y, R288H, G308D, T327I, and IVS6-12C-->G. Two
      new polymorphisms, 2033C>T and 2059C>T, were identified in intron 6 which, in
      combination with two polymorphisms previously described (2161C>G and 2213C>G),
      gave rise to four different haplotypes in the control population. In addition, we
      also studied polymorphism 842G>T. Linkage disequilibrium was detected between
      mutations IVS2+1G-->A, D255H, and T327I and specific haplotypes, suggesting a
      unique origin for these mutations. Moreover, mutation T327I was always associated
      with the T allele of the new rare variant A210A (893C>T). The distribution of
      mutation D255H (frequency 19.4%) among patients with different MLD clinical
      presentation revealed a clear genotype-phenotype correlation paralleling that
      reported for mutation IVS2+1G-->A (frequency 25%). Among the novel mutations,
      only P136S and R288H occurred on a background of the ARSA pseudodeficiency
      allele. Screening 182 normal chromosomes identified a frequency of 8.8% of this
      allele; moreover, we identified two unrelated subjects with the polyA- mutation
      in the absence of the N350S mutation, and this infrequent haplotype reinforced
      the heterogeneity of conditions with ARSA deficiency.
CI  - Copyright 1999 Wiley-Liss, Inc.
FAU - Gort, L
AU  - Gort L
AD  - Institut de Bioquimica Clinica, Barcelona, Spain.
FAU - Coll, M J
AU  - Coll MJ
FAU - Chabas, A
AU  - Chabas A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hum Mutat
JT  - Human mutation
JID - 9215429
RN  - 0 (Sulfoglycosphingolipids)
RN  - EC 3.1.6.8 (Cerebroside-Sulfatase)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Age of Onset
MH  - Alleles
MH  - Cells, Cultured
MH  - Cerebroside-Sulfatase/*genetics/metabolism
MH  - Child
MH  - Child, Preschool
MH  - Chromosome Mapping
MH  - Chromosomes, Human, Pair 22/genetics
MH  - DNA Mutational Analysis
MH  - Female
MH  - Fibroblasts/enzymology
MH  - Gene Frequency
MH  - Haplotypes/genetics
MH  - Humans
MH  - Infant
MH  - Leukodystrophy, Metachromatic/diagnosis/*enzymology/genetics
MH  - Male
MH  - Mutation
MH  - Phenotype
MH  - Polymerase Chain Reaction
MH  - Polymorphism, Genetic/genetics
MH  - Polymorphism, Single-Stranded Conformational
MH  - Spain
MH  - Sulfoglycosphingolipids/urine
EDAT- 1999/09/08 00:00
MHDA- 1999/09/08 00:01
CRDT- 1999/09/08 00:00
PHST- 1999/09/08 00:00 [pubmed]
PHST- 1999/09/08 00:01 [medline]
PHST- 1999/09/08 00:00 [entrez]
AID - 10.1002/(SICI)1098-1004(1999)14:3<240::AID-HUMU7>3.0.CO;2-L [pii]
AID - 10.1002/(SICI)1098-1004(1999)14:3<240::AID-HUMU7>3.0.CO;2-L [doi]
PST - ppublish
SO  - Hum Mutat. 1999;14(3):240-8. doi:
      10.1002/(SICI)1098-1004(1999)14:3<240::AID-HUMU7>3.0.CO;2-L.