GM1 gangliosidosis and Morquio B disease: expression analysis of missense mutations affecting the catalytic site of acid β‐galactosidase |
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| Authors: | Doris Hofer Karl Paul Katrin Fantur Michael Beck Friederike Bürger Catherine Caillaud Ksenija Fumic Jana Ledvinova Agnieszka Lugowska Helen Michelakakis Briguita Radeva Uma Ramaswami Barbara Plecko Eduard Paschke |
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| Institution: | 1. Department of Paediatrics, Medical University of Graz, Austria;2. Children's Hospital, University of Mainz, Lysosomal Disorder Working Group, Germany;3. University Children's Hospital, Centre for Metabolic Diseases Heidelberg, Germany;4. Service de Biochimie et Génétique Moléculaire, Groupe Hospitalier Cochin ‐ Saint‐Vincent‐de‐Paul, Assistance Publique‐H?pitaux de Paris, France;5. Clinical Institute of Laboratory Diagnosis, Zagreb University School of Medicine, Zagreb, Croatia;6. Charles University in Prague, 1st Medical Faculty, Institute of Inherited Metabolic Disorders of 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic;7. Institute of Psychiatry and Neurology, Department of Genetics, Warsaw, Poland;8. Division of Enzymology and Cellular Function, Institute of Child Health, Agia Sophia Children's Hospital, Athens, Greece;9. Department of Clinical Genetics, Medical University of Sofia, Bulgaria;10. Department of Paediatric Endocrinology, Diabetes and Metabolism, Addenbrooke's Hospital, Cambridge, United Kingdom |
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| Abstract: | Alterations in GLB1, the gene coding for acid β‐D‐galactosidase (β‐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 β‐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 β‐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. Hum Mutat 30, 1–8, 2009. © 2009 Wiley‐Liss, Inc. |
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| Keywords: | GLB1 GM1 gangliosidosis mucopolysaccharidosis type IVB phenotype– genotype relations |
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