PMID- 10381328
OWN - NLM
STAT- MEDLINE
DCOM- 19990921
LR  - 20081121
IS  - 1096-7192 (Print)
IS  - 1096-7192 (Linking)
VI  - 67
IP  - 3
DP  - 1999 Jul
TI  - Metachromatic leukodystrophy: subtype genotype/phenotype correlations and
      identification of novel missense mutations (P148L and P191T) causing the
      juvenile-onset disease.
PG  - 206-12
AB  - Metachromatic leukodystrophy (MLD) is a lysosomal storage disease resulting from 
      the deficient activity of arylsulfatase A (ASA) and the accumulation of
      sulfatides. The disease is characterized by several subtypes, designated by age
      at onset: the late-infantile-, juvenile-, and adult-onset variants. Mutation
      analysis of genomic DNA from a proband with each variant was performed to
      identify and characterize their causative ASA mutations. Two sisters with the
      infantile-onset disease were homoallelic for the missense mutation D335V, a
      juvenile-onset proband was heteroallelic for two novel missense mutations, P148L 
      and P191T, and an adult-onset patient was heteroallelic for the H397Y and P426L
      mutations. The novel mutations were not identified in 108 normal alleles
      indicating that these base substitutions were not common polymorphisms. To
      further characterize the mutant gene products, the mutant enzymes were partially 
      purified from cultured fibroblasts and their molecular weights and charges were
      compared by immunoblotting following SDS-PAGE or isoelectric focusing (IEF).
      Normal fibroblast ASA had a single, broad band at 54 kDa. The enzyme from the
      late-infantile-onset patient had distinct bands of 36 and 78 kDa, but lacked the 
      normal 54-kDa species. The juvenile- and adult-onset patients each had a faint
      band of 54 kDa and several other bands ranging from 29 to 64 kDa. IEF revealed
      several bands for the partially purified normal enzyme with a relatively narrow
      pH range around 4.0, whereas numerous bands with a wider range of isoelectric
      points were observed with the enzymes from the juvenile- and adult-onset
      fibroblasts. In contrast, the enzyme from the late-infantile-onset proband had
      four bands with more acidic isoelectric points, none corresponding to those of
      the normal enzyme. These results document changes in both size and charge of the 
      mutant enzymes from patients with different mutations and MLD subtypes.
CI  - Copyright 1999 Academic Press.
FAU - Qu, Y
AU  - Qu Y
AD  - H.A. Chapman Institute of Medical Genetics, Tulsa, Oklahoma, 74135, USA.
FAU - Shapira, E
AU  - Shapira E
FAU - Desnick, R J
AU  - Desnick RJ
LA  - eng
GR  - 1 P30 HD 28822/HD/NICHD NIH HHS/United States
GR  - 5 R37 DK34045/DK/NIDDK NIH HHS/United States
GR  - R MO1 RROO071/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Genet Metab
JT  - Molecular genetics and metabolism
JID - 9805456
RN  - 0 (Oligonucleotides)
RN  - EC 3.1.6.8 (Cerebroside-Sulfatase)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Age of Onset
MH  - *Alleles
MH  - Base Sequence
MH  - Cerebroside-Sulfatase/*genetics/isolation & purification
MH  - Electrophoresis, Polyacrylamide Gel
MH  - Female
MH  - Genetic Variation
MH  - Genotype
MH  - Humans
MH  - Immunoblotting
MH  - Infant
MH  - Isoelectric Focusing
MH  - Leukodystrophy, Metachromatic/classification/*genetics
MH  - Molecular Sequence Data
MH  - *Mutation, Missense
MH  - Oligonucleotides/genetics
MH  - Phenotype
MH  - Sequence Analysis, DNA
EDAT- 1999/06/25 00:00
MHDA- 1999/06/25 00:01
CRDT- 1999/06/25 00:00
PHST- 1999/06/25 00:00 [pubmed]
PHST- 1999/06/25 00:01 [medline]
PHST- 1999/06/25 00:00 [entrez]
AID - 10.1006/mgme.1999.2865 [doi]
AID - S1096-7192(99)92865-2 [pii]
PST - ppublish
SO  - Mol Genet Metab. 1999 Jul;67(3):206-12. doi: 10.1006/mgme.1999.2865.