Genetic Heterogeneity in Type 1 Gaucher Disease: Multiple Genotypes in Ashkenazic and Non-Ashkenazic Individuals

Nucleotide sequence analysis of a genomic clone from an Ashkenazic Jewish patient with type 1 Gaucher disease revealed a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change results in the amino acid substitution of serine for asparagine. Tra...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1988-04, Vol.85 (7), p.2349-2352
Main Authors: Tsuji, Shoji, Martin, Brian M., Barranger, John A., Stubblefield, Barbara K., LaMarca, Mary E., Ginns, Edward I.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Alleles
AMIDES
Amino Acid Sequence
AMINO ACIDS
ANIMAL CELLS
ASPARAGINE
Base Sequence
BASIC BIOLOGICAL SCIENCES
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOCHEMISTRY
Biological and medical sciences
CARBOXYLIC ACIDS
CHEMISTRY
Child
Child, Preschool
Complementary DNA
CONNECTIVE TISSUE CELLS
DAYS LIVING RADIOISOTOPES
DIAGNOSIS
DISEASES
DNA
DNA HYBRIDIZATION
DNA probes
ENZYME ACTIVITY
ENZYMES
Errors of metabolism
Exons
FIBROBLASTS
Gaucher disease
Gaucher Disease - classification
Gaucher Disease - enzymology
Gaucher Disease - genetics
GENE MUTATIONS
Genetic mutation
Genomics
Genotype
Glucosidases - genetics
Glucosylceramidase - deficiency
Glucosylceramidase - genetics
HEREDITARY DISEASES
HUMAN POPULATIONS
Humans
HYBRIDIZATION
HYDROLASES
HYDROXY ACIDS
Infant
ISOTOPES
Jews
LIGHT NUCLEI
Lipids (lysosomal enzyme disorders, storage diseases)
Medical sciences
METABOLIC DISEASES
Middle Aged
Molecular Sequence Data
MUTAGENESIS
Mutation
MUTATIONS
NERVOUS SYSTEM DISEASES
NUCLEI
NUCLEIC ACIDS
ODD-ODD NUCLEI
Oligonucleotide probes
OLIGONUCLEOTIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PATIENTS
PEPTIDE HYDROLASES
PHENOTYPE
PHOSPHORUS 32
PHOSPHORUS ISOTOPES
POPULATIONS
RADIOISOTOPES
RFLPS
Risk
SERINE
SOMATIC CELLS 550401 > Genetics-- Tracer Techniques
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Description
Summary:Nucleotide sequence analysis of a genomic clone from an Ashkenazic Jewish patient with type 1 Gaucher disease revealed a single-base mutation (adenosine to guanosine transition) in exon 9 of the glucocerebrosidase gene. This change results in the amino acid substitution of serine for asparagine. Transient expression studies following oligonucleotide-directed mutagenesis of the normal cDNA confirmed that the mutation results in loss of glucocerebrosidase activity. Allele-specific hybridization with oligonucleotide probes demonstrated that this mutation was found exclusively in the type 1 phenotype. None of the 6 type 2 patients, 11 type 3 patients, or 12 normal controls had this allele. In contrast, 15 of 24 type 1 patients had one allele with this mutation, and 3 others were homozygous for the mutation. Furthermore, some of the Ashkenazic Jewish type 1 patients had only one allele with this mutation, suggesting that even in this population there is allelic heterozygosity. These findings indicate that there are multiple allelic mutations responsible for type 1 Gaucher disease in both the Jewish and non-Jewish populations. Allelic-specific hybridization demonstrating this mutation in exon 9, used in conjunction with the Nci I restriction fragment length polymorphism described as a marker for neuronopathic Gaucher disease, provides a tool for diagnosis and genetic counseling that is ≈ 80% informative in all Gaucher patients studied.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.85.7.2349