A mutation in arylsulfatase B gene causes mucopolysuccharidosis VI in rats
- Mt. Sinai School of Medicine, New York, NY (United States); and others
Mucopolysuccharidosis (MPS) type VI comprises a group of autosomal recessive disorders caused by the deficiency of arylsulfatase B (ARSB) and subsequent lysosomal storage of glucosaminoglycans. We have identified a mutant rat strain that has remarkable similarites to human MPS VI. Recently, we have localized the autosomal recessive gene for the mutant phenotype on rat chromosome 2 by linkage analysis. The rat chromosome 2 is syntenic with the human and mouse chromosomes on which ARSB genes were assigned. Thus the mutant rats were expected to have a mutation in the ARSB gene. A normal rat liver cDNA library was screened using the cat ARSB cDNA as a probe, and clones which cover almost all of the complete ARSB open reading frame were isolated. The nucleotide sequence and amino acid sequence of the rat ARSB sequence showed 80% and 85% similarities with the human ARSB gene, respectively. The ARSB gene was assigned to rat chromosome 2 by using a rat-mouse hybrid cell panel, confirming the linkage analysis. Based on the nucleotide sequence of the normal rat ARSB gene, RT-PCR using liver RNA of the mutant rat was carried out to isolate the cDNA of the mutant rat ARSB gene. By sequencing several independent clones, the cDNA of the mutant rat was found to have a one base insertion at nucleotide 507, resulting in a frameshift mutation in the coding region of the rat ARSB gene, which introduces a stop codon in position 258 of the putative ARSB polypeptide. All affected MPS VI rats were homozygous for the mutant allele, while all phenotypically normal rats were heterozygous or homozygous for the wild type allele, indicating a perfect correspondence between the MPS VI phenotype and the genotype of the mutation. We conclude that the mutation in the ARSB gene is responsible for MPS VI in the rat, and that the mutant rat is an excellent model for study of human MPS VI pathogenesis and treatment.
- OSTI ID:
- 134241
- Report Number(s):
- CONF-941009--
- Journal Information:
- American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
AMINO ACIDS
BIOLOGICAL MODELS
CHROMOSOMES
CODONS
CONGENITAL MALFORMATIONS
CORRELATIONS
DNA SEQUENCING
DNA-CLONING
GENE MUTATIONS
GENES
GENETIC MAPPING
GENOTYPE
HEREDITARY DISEASES
HYBRIDIZATION
LYSOSOMES
METABOLIC DISEASES
NUCLEOTIDES
PATIENTS
PHENOTYPE
POLYMERASE CHAIN REACTION
PROBES
RATS
RECESSIVE MUTATIONS
STORAGE