Naslov
GM1 gangliosidosis and Morquio B disease : expression analysis of missense mutations affecting the catalytic site of acid -galactosidase

Autori
Hofer, Doris ; Paul, Karl ; Fantur, Katrin ; Beck, Michael ; Bürger, Friederike ; Caillaud, Catherine ; Fumić, Ksenija ; Ledvinova, Jana ; Lugowska, Agnieszka ; Michelakakis, Helen ; Radeva, Briguita ; Ramaswami, Uma ; Plečko, Barbara ; Paschke, Eduard

Izvornik
Human mutation (1059-7794) 30 (2009), 8; 1214-1221

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
GLB1 • GM1 gangliosidosis • mucopolysaccharidosis type IVB • phenotype-genotype relations

Sažetak
Alterations in GLB1, the gene coding for acid -D-galactosidase (-Gal), can result in GM1 gangliosidosis (GM1), a neurodegenerative disorder, or in Morquio B disease (MBD), a phenotype with dysostosis multiplex and normal central nervous system (CNS) function. While most MBD patients carry a common allele, c.817TG>CT (p.W273L), only few of the >100 mutations known in GM1 can be related to a certain phenotype. In 25 multiethnic patients with GM1 or MBD, 11 missense mutations were found as well as one novel insertion and a transversion causing aberrant gene products. Except c.602G>A (p.R201H) and two novel alleles, c.592G>T (p.D198Y) and c.1189C>G (p.P397A), all mutants resulted in significantly reduced -Gal activities (<10% of normal) upon expression in COS-1 cells. Although c.997T>C (p.Y333H) expressed 3% of normal activity, the mutant protein was localized in the lysosomal-endosomal compartment. A homozygous case presented with late infantile GM1, while a heterozygous, juvenile case carried p.Y333H together with p.R201H. This allele, recently found in homozygous MBD, gives rise to rough endoplasmic reticulum (RER)-located -Gal precursors. Thus, unlike classical MBD, the phenotype of heterozygotes carrying p.R201H may rather be determined by poorly active, properly transported products of the counter allele than by the mislocalized p.R201H precursors.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti, Kliničke medicinske znanosti

POVEZANOST RADA