Abstract
BackgroundBeta‐galactosidase‐1 ( GLB1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB1 cause two different lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB. In GM1 gangliosidosis, decreased β‐galactosidase‐1 enzymatic activity leads to the accumulation of GM1 gangliosides, predominantly within the CNS. We present a 22‐month‐old proband with GM1 gangliosidosis type II (late‐infantile form) in whom a novel homozygous in‐frame deletion (c.1468_1470delAAC, p.Asn490del) in GLB1 was detected.MethodsWe 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.ResultsMolecular 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 GLB1 enzymatic activity (~3% of normal activity) in the proband.ConclusionsWe have described a novel, pathogenic in‐frame deletion of GLB1 in a patient with GM1 gangliosidosis type II.
Highlights
Pathogenic alterations in GLB1 lead to a reduction in affinity for at least one substrate, resulting in either the toxic accumulation of GM1 ganglioside in the nervous system leading to progressive neurological deterioration (GM1 gangliosidosis) or defective storage of galactosyl oligosaccharides and keratin sulfate causing mucopolysaccharidosis type IVB, Morquio type (MIM: 253010) (Regier & Tifft, 1993)
In GM1 gangliosidosis, defective β‐galactosidase‐1 causes cell lysosomes to accumulate GM1 ganglioside and other glycoconjugates over time—a process that has the most pronounced effects on the central nervous system (CNS) since gangliosides are abundant in the neuronal plasma membrane (Posse de Chaves & Sipione, 2010)
GM1 gangliosidosis is divided into three types that generally correlate with residual enzyme activity, of which type I (MIM: 230500) is the most severe and has the earliest onset (Regier and Tifft, 1993)
Summary
Pathogenic alterations in GLB1 lead to a reduction in affinity for at least one substrate, resulting in either the toxic accumulation of GM1 ganglioside in the nervous system leading to progressive neurological deterioration (GM1 gangliosidosis) or defective storage of galactosyl oligosaccharides and keratin sulfate causing mucopolysaccharidosis type IVB, Morquio type (MIM: 253010) (Regier & Tifft, 1993). GM1 gangliosidosis is divided into three types that generally correlate with residual enzyme activity, of which type I (MIM: 230500) is the most severe and has the earliest onset (Regier and Tifft, 1993). Type I symptoms appear before 1 year of age and present with CNS dysfunction, psychomotor regression, “coarse” facial features, cardiac involvement, skeletal abnormality, macular cherry‐red spots, and hepatosplenomegaly (Caciotti et al, 2011).
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have