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Complex arylsulfatase A alleles causing metachromatic leukodystrophy
Author(s) -
Kappler Joachim,
Sommerlade Hans Jörg,
von Figura Kurt,
Gieselmann Volkmar
Publication year - 1994
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.1380040205
Subject(s) - metachromatic leukodystrophy , arylsulfatase a , biology , missense mutation , genetics , compound heterozygosity , allele , lysosomal storage disease , leukodystrophy , mutation , arylsulfatase , hurler syndrome , microbiology and biotechnology , gene , enzyme , biochemistry , disease , medicine
Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of a patient affected with late infantile metachromatic leukodystrophy revealed that the patient is a compound heterozygote of two alleles carrying two deleterious mutation each. One allele bears a splice donor site mutation together with two polymorphisms and an additional missense mutation (Gly 122>Ser). The splice donor site mutation and the Gly 122>Ser substitution have been described recently but on different alleles. The other allele carries two missense mutations causing a Gly 154>Asp and a Pro 167>Arg substitution. When arylsulfatase A cDNAs carrying these mutations separately or in combination were transfected into baby hamster kidney cells expression of arylsulfatase A activity could not be detected. Linkage of mutations was verified by sequencing of the parental DNAs. Biosynthesis studies performed with the patients' fibroblasts show that the enzyme carrying both mutations is synthesized in almost normal amounts but is rapidly degraded in an early biosynthetic compartment. The occurence of two disease causing mutations on the same allele is a novel phenomenon in metachromatic leukodystrophy and as far as lysosomal storage diseases are concerned have so far only been described in Fabry disease and in the complex glucocerebrosidase alleles associated with Gaucher disease. © 1994 Wiley‐Liss, Inc.