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

Abstract

Gaucher disease results from the deficiency of the lysosomal enzyme glucocerebrosidase (EC 3.2.1.45). Although the functional gene for glucocerebrosidase (GBA) and its pseudogene (psGBA), located in close proximity on chromosome 1q21, have been studied extensively, the flanking sequence has not been well characterized. The recent identification of human metaxin (MTX) immediately downstream of psGBA prompted a closer analysis of the sequence of the entire region surrounding the GBA gene. We now report the genomic DNA sequence and organization of a 75-kb region around GBA, including the duplicated region containing GBA and MTX. The origin and endpoints of the duplication leading to the pseudogenes for GBA and MTX are now clearly established. We also have identified three new genes within the 32 kb of sequence upstream to GBA, all of which are transcribed in the same direction as GBA. Of these three genes, the gene most distal to GBA is a protein kinase (clk2). The second gene, propin1, has a 1.5-kb cDNA and shares homology to a rat secretory carrier membrane protein 37

Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian gaucher patients

“…The role of modifying genetic or nongenetic factors influencing the GD phenotypes, has been widely discussed (Boot et al, 1997;Grabowski, 1997;Germain et al, 1998;Koprivica et al, 2000). The contribution of the flanking genes at GBA locus (Winfield et al, 1997) was postulated as well as a possible influence of polymorphisms in cis on mutant alleles was hypothesized as suggested for cystic fibrosis and Krabbe disease (Cuppens et al, 1998;Luzi et al, 2001). Recently, lysosomal-associated membrane protein-1 (LAMP-1), saposin C and glycolipid substrates were studied in GD patients and a relationship was found among substrates ratio, LAMP-1, saposin C levels, and patient phenotype (Whitfield et al, 2002).…”

Ectopic Overexpression of COTE1 Promotes Cellular Invasion of Hepatocellular Carcinoma

“…The variant 2 and 3 lack an in-frame portion of the 5' coding region compared to variant 1, the resulting proteins (isoform b and c) are shorter than isoform a (NCBI Reference Sequences). The protein COTE1 includes 669 amino acids with two potential N-glycosylationsites, a leucine zipper, and multiple potential phosphorylation sites and N-myristoylationsites (Winfield et al, 1997). The recent data showed COTE1 contains a predicted fourtransmembrane domains, making it possible that it would reside in a membrane-bound subcellular organelle such as the Golgi (Ludes-Meyers et al, 2004).…”

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

“…It was widely anticipated that the elucidation of the GBA sequence would yield an explanation of the vast phenotypic differences encountered among patients with GD. During the past two decades, there have been significant advances in understanding the organization of the gene and locus [Winfield et al, 1997], the identification of mutant alleles [Beutler and Gelbart, 1993;Grabowski and Horowitz, 1997;Tsuji et al, 1987], the enzyme structure [Dvir et al, 2003], and genotype-phenotype correlations [Beutler, 1992;Grabowski, 1997;Koprivica et al, 2000;Sidransky et al, 1994;Zimran et al, 1989]. Nevertheless, the pathological mechanisms through which the mutant enzyme acts to cause the diverse range of patient phenotypes are still elusive.…”

“…Metaxin also has a pseudogene, which is located in the 16-kb region between GBA and GBAP. Both pseudogenes appear to have resulted from a duplication of the region, and are present in primates, but not in other species [Martinez-Arias et al, 2001a;Winfield et al, 1997]. The sequences of both GBA and MTX1 have been shown through multispecies comparative sequence analyses [Thomas et al, 2003] to have conservation of the exonic regions in humans and nine mammalian species [LaMarca et al, 2004].…”

“…1A) [Long et al, 1996;Winfield et al, 1997]. The closest downstream gene is metaxin (MTX1), which is transcribed convergently to GBA [Long et al, 1996].…”