Genetic fine localization of the β-glucocerebrosidase ( GBA ) and prosaposin ( PSAP ) genes: implications for Gaucher disease

Abstract

Mutations in the glucocerebrosidase (GBA) and prosaposin (PSAP) genes are responsible for Gaucher disease, the most prevalent sphingolipidosis. Somatic cell hybrid analysis and in situ hybridization experiments have localized the GBA gene to 1q21 and the PSAP gene to 10q21-q22. We performed pairwise and multi-point linkage analyses between the two genes and several highly polymorphic markers from the Généthon human linkage map. Our results show that six markers cosegregate with the GBA gene (Zmax = 8.73 at theta = 0.00 for marker D1S2714) and define a 3.2-cM interval between D1S305 and D1S2624 as the most probable location for the gene. Three of these markers (D1S2777, D1S303, and D1S2140), as well as the gene encoding pyruvate kinase (PKLR), are contained in a single YAC clone together with the GBA gene. A new polymorphism was identified within the PSAP gene (C16045T) and used for linkage studies. The multi-point analysis places the gene in a 9.8-cM interval between D10S1688 and D10S607. The fine localization of these genes provides a useful tool for cosegregation analysis, indirect molecular diagnosis, and population genetic studies.

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

“…Each of these sequence variations are in linkage disequilibrium and constitute two major haplotypes [Beutler et al, 1992b]. The haplotypes, Pv1.1 -and Pv1.1 1 , occur with frequencies of roughly 70% and 30% in the Caucasian population, respectively, with inverted frequencies in Asian and African populations [Cormand et al, 1997b;Glenn et al, 1994;Masuno et al, 1989;Mateu et al, 2002;Sorge et al, 1985a]. Mutation c.1226A4G (N370S) is in linkage disequilibrium with the Pv1.1 -haplotype [Amaral et al, 1997;Cormand et al, 1998a;Lacerda et al, 1994;Rockah et al, 1998;Zimran et al, 1990a], while c.84dupG is found with Pv1.1 1 (Beutler et al, 1992b;Rockah et al, 1998;Zimran et al, 1990a].…”

Gaucher Disease

“…11 More than 200 distinct GBA gene mutations are described (Human Gene Mutation Database www.hgmd.cf.ac.uk). Majority of these mutations are single nucleotide substitutions.…”

Identification of Three Additional Genes Contiguous to the Glucocerebrosidase Locus on Chromosome 1q21: Implications for Gaucher Disease

“…A highly homologous pseudogene (psGBA) is located nearby , and has contributed significantly to the origin of mutations in GBA (Tsuji et al 1987). Cormand et al (1997) have recently provided a localization of this region relative to six markers from the Généthon human linkage map. Analyses of the mutations present in patients have revealed both single missense mutations (Beutler and Gelbart 1997) and other recombinant alleles, including several mutations that originate from the pseudogene sequence (Eyal et al 1990;Latham et al 1990).…”