Protein modeling and clinical description of a novel in-frame GLB1 deletion causing GM1 gangliosidosis type II

Richter Jr., J. E., Zimmermann, M. T., Blackburn, P. R., Mohammad, A. N., Klee, E. W., Pollard, L. M., Macmurdo, C. F., Atwal, P. S. and Caulfield, T. R. (2018) Protein modeling and clinical description of a novel in-frame GLB1 deletion causing GM1 gangliosidosis type II. Molecular Genetics and Genomic Medicine, 6(6), pp. 1229-1235. (doi: 10.1002/mgg3.454) (PMID:30187681) (PMCID:PMC6305665)

Abstract

Background: Beta‐galactosidase‐1 ( GLB 1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM 1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB 1 cause two different lysosomal storage disorders: GM 1 gangliosidosis and mucopolysaccharidosis type IVB . In GM 1 gangliosidosis, decreased β‐galactosidase‐1 enzymatic activity leads to the accumulation of GM 1 gangliosides, predominantly within the CNS . We present a 22‐month‐old proband with GM 1 gangliosidosis type II (late‐infantile form) in whom a novel homozygous in‐frame deletion (c.1468_1470delAAC , p.Asn490del) in GLB 1 was detected. Methods: We used an experimental protein structure of β‐galactosidase‐1 to generate a model of the p.Asn490del mutant and performed molecular dynamic simulations to determine whether this mutation leads to altered ligand positioning compared to the wild‐type protein. In addition, residual mutant enzyme activity in patient leukocytes was evaluated using a fluorometric assay. Results: Molecular dynamics simulations showed the deletion to alter the catalytic site leading to misalignment of the catalytic residues and loss of collective motion within the model. We predict this misalignment will lead to impaired catalysis of β‐galactosidase‐1 substrates. Enzyme assays confirmed diminished GLB 1 enzymatic activity (~3% of normal activity) in the proband. Conclusions: We have described a novel, pathogenic in‐frame deletion of GLB 1 in a patient with GM 1 gangliosidosis type II .

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Atwal, Dr Paldeep
• Authors: Richter Jr., J. E., Zimmermann, M. T., Blackburn, P. R., Mohammad, A. N., Klee, E. W., Pollard, L. M., Macmurdo, C. F., Atwal, P. S., and Caulfield, T. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Molecular Genetics and Genomic Medicine
• Publisher: Wiley
• ISSN: 2324-9269
• ISSN (Online): 2324-9269
• Published Online: 05 September 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Molecular Genetics and Genomic Medicine 6(6): 1229-1235
• Publisher Policy: Reproduced under a Creative Commons License