Molecular Aspects of Gaucher Disease

Abstract

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.

Molecular screening of Japanese patients with gaucher disease: Phenotypic variability in the same genotypes

“…The 1448C mutation has been found in patients in all ethnic populations (Theophilus et al, 1989;Firon et al, 1990). Our results show that the frequency of the 1448C mutation in Japanese patients is similar to that of other ethnic groups (Levy et al, 1991). The phenotype-genotype relationships concerning this mutation are a little complex because of methods of mutation analysis, such as whether by screening for only this mutation site or by sequencing of entire coding region.…”

Gaucher type 2 disease: Identification of a novel transversion mutation in a French-Irish patient

“…A homozygous T to C transition at glucocerebrosidase cDNA nucleotide position 1448, which results in L444P, is frequently found in Gaucher disease patients with neurological involvement. This mutation can result from either a single base substitution [Theophilus et al, 1989;Tsuji et al, 1987] or an unequal crossingover between the glucocerebrosidase functional gene and pseudogene creating a fusion gene or complex allele [Latham et al, 1990;Levy et al, 1991;Zimran et al, 1990]. It was postulated that a T to C single base substitution will result in type 3 Gaucher disease, whereas the complex allele will result in the type 2 form [Latham et al, 1990;Dahl et al, 1990].…”

Letter to the editor

“…A T+C transition mutation at cDNA nucleotide 1448 (genomic nt 6433) that results in 444Le~+444Pro has frequently been found among patients with type 2 and type 3 Gaucher disease (3). This T6433C mutation may result from a single base substitution (3,4) or an uneven crossing-over between the functional gene and pseudogene of glucocerebrosidase that creates a "complex allele" (5)(6)(7). While the base substitution in the homozygous form was demonstrated to be the only mutation detected in patients with type 3 Gaucher disease in Sweden ( 8 ) , a number of type 2 Gaucher disease patients were found to be genetic compounds; i.e., they are heterozygous for this base substitution and the complex allele (5,6).…”

“…This T6433C mutation may result from a single base substitution (3,4) or an uneven crossing-over between the functional gene and pseudogene of glucocerebrosidase that creates a "complex allele" (5)(6)(7). While the base substitution in the homozygous form was demonstrated to be the only mutation detected in patients with type 3 Gaucher disease in Sweden ( 8 ) , a number of type 2 Gaucher disease patients were found to be genetic compounds; i.e., they are heterozygous for this base substitution and the complex allele (5,6). It was also reported that the complex allele in the homozygous form is incompatible with life and results in spontaneous abortion during early fetal development (9).…”