Single-stranded cDNA was prepared from RNA obtained from a patient with type 1 Gaucher disease. The cDNA was amplified in vitro and analyzed by sequencing. Three base-pair changes were identified which included a G to C transversion at nucleotide 3119 of the active gene (Asp140----His), an A to C transversion at nucleotide 3170 (Lys157----Gln) and a G to A change at nucleotide 5309 (Glu326----Lys). To study the mode of inheritance of the three different base-pair changes, genomic DNA was prepared from blood or skin fibroblasts of several family members. Genomic glucocerebrosidase DNA sequences were amplified and subjected to hybridization with allele-specific oligonucleotides (ASOs). The hybridization profiles demonstrated that two of the base-pair changes originated from the mother and were transmitted to her two affected sons and to a grandchild, while the third base-pair change, originating from the father, was transmitted to his two affected sons, a carrier daughter and a second grandchild. Tests of other patients with Gaucher disease failed to disclose the presence of the three base-changes. This is a unique family with three base-pair changes tightly linked to Gaucher disease.
Gaucher disease is the most common sphingolipid storage disorder. Due to its high prevalence it may appear with a nonrelated neurological disease and be misinterpreted as Gaucher type 3. A family is described in which 2 Gaucher brothers presented different clinical signs. Molecular analysis has shown that both carried two mutated alleles. One allele had a G to C transversion at nucleotide 3119 of the active gene (Asp140-His) while the other presented two base pair changes, an A to C transversion at nucleotide number 3170 (Lys157-Gly), and a G–A transition at nucleotide number 5309 (Glu324-Lys). Therefore, both presented the same type of Gaucher disease which was accompanied with a nonrelated neurological disease in one of them. Molecular diagnosis of 161 patients has provided a relative abundance of different mutations among Jewish and non-Jewish patients and allowed some genotype-phenotype correlation. Differential expression of the murine glucocerebrosidase activator gene (the prosaposine) has been demonstrated using Northern technique and in situ hybridization. High expression levels were observed in the brain and testes. In the testes the prosaposine expression was confined to the supporting cells. In the female gonad prosaposine expression has also been shown, in the corpus luteum. In a 12½-day-old embryo, prosaposine gene expression was detected mainly in brain stem, in dorsal ganglia and in the genital ridge.
We found normal individuals whose aspartoacylase gene Y231X mutation site consistently gave no signal in a primer extension assay. We determined the nucleotide sequence of the relevant region of the gene in those individuals, and found a new allele with a thymidine residue at the mutation site instead of a cytidine. Since both TAC and TAT code for tyrosine, this sequence polymorphism has no effect on the amino acid sequence of the ASPA protein. We found the relative frequencies of the 693C and the 693T alleles in the tested population to be 0.75 and 0.25 respectively.
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