Open AccessProtein modeling and clinical description of a novel in‐frame GLB 1 deletion causing GM 1 gangliosidosis type II
Author(s) -
Richter John E.,
Zimmermann Michael T.,
Blackburn Patrick R.,
Mohammad Ahmed N.,
Klee Eric W.,
Pollard Laura M.,
Macmurdo Colleen F.,
Atwal Paldeep S.,
Caulfield Thomas R.
Publication year - 2018
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.454
Subject(s) - gangliosidosis , hydrolase , mutant , enzyme , wild type , chemistry , lysosomal storage disease , biology , microbiology and biotechnology , biochemistry , gene
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_1470del AAC , 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 .