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

ABSTRACT: BACKGROUND:Beta-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 ?-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. METHODS:We used an experimental protein structure of ?-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 ?-galactosidase-1 substrates. Enzyme assays confirmed diminished GLB1 enzymatic activity (~3% of normal activity) in the proband. CONCLUSIONS:We have described a novel, pathogenic in-frame deletion of GLB1 in a patient with GM1 gangliosidosis type II.

SUBMITTER: Richter JE

PROVIDER: S-EPMC6305665 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Richter John E JE Zimmermann Michael T MT Blackburn Patrick R PR Mohammad Ahmed N AN Klee Eric W EW Pollard Laura M LM Macmurdo Colleen F CF Atwal Paldeep S PS Caulfield Thomas R TR

Molecular genetics & genomic medicine 20180905 6

<h4>Background</h4>Beta-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 proban ...[more]

PMID: 30187681

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Project description:Type II or juvenile GM1-gangliosidosis is an autosomal recessive lysosomal storage disorder, which is clinically distinct from infantile form of the disease by the lack of characteristic cherry-red spot and hepatosplenomegaly. The disease is characterized by slowly progressive neurodegeneration and mild skeletal changes. Due to the later age of onset and uncharacteristic presentation, diagnosis is frequently puzzled with other ataxic and purely neurological disorders. Up to now, 3-4 types of GM1-gangliosidosis have been reported and among them type I is the most common phenotype with the age of onset around 6 months. Various forms of GM1-gangliosidosis are caused by GLB1 gene mutations but severity of the disease and age of onset are directly related to the position and the nature of deleterious mutations. However, due to its unique genetic cause and overlapping clinical features, some researchers believe that GM1 gangliosidosis represents an overlapped disease spectrum instead of four distinct types.Here, we report a less frequent type of autosomal recessive GM1 gangliosidosis with perplexing clinical presentation in three families in the southwest part of Iran, who are unrelated but all from "Lurs" ethnic background. To identify disease-causing mutations, Whole Exome Sequencing (WES) utilizing next generation sequencing was performed. Four patients from three families were investigated with the age of onset around 3 years old. Clinical presentations were ataxia, gate disturbances and dystonia leading to wheelchair-dependent disability, regression of intellectual abilities, and general developmental regression. They all were born in consanguineous families with no previous documented similar disease in their parents. A homozygote missense mutation in GLB1 gene (c. 601 G?>?A, p.R201C) was found in all patients. Using Sanger sequencing this identified mutation was confirmed in the proband, their parents, grandparents, and extended family members, confirming its autosomal recessive pattern of inheritance.Our study identified a rare pathogenic missense mutation in GLB1 gene in patients with complex neurodevelopmental findings, which can extend the list of differential diagnoses for childhood ataxia in Iranian patients.

Project description:Introduction:GM1 gangliosidosis is a rare autosomal recessive genetic disorder caused by the disruption of the GLB1 gene that encodes ?-galactosidase, a lysosomal hydrolase that removes ?-linked galactose from the non-reducing end of glycans. Deficiency of this catabolic enzyme leads to the lysosomal accumulation of GM1 and its asialo derivative GA1 in ?-galactosidase deficient patients and animal models. In addition to GM1 and GA1, there are other glycoconjugates that contain ?-linked galactose whose metabolites are substrates for ?-galactosidase. For example, a number of N-linked glycan structures that have galactose at their non-reducing end have been shown to accumulate in GM1 gangliosidosis patient tissues and biological fluids. Objective:In this study, we attempt to fully characterize the broad array of GLB1 substrates that require GLB1 for their lysosomal turnover. Results:Using tandem mass spectrometry and glycan reductive isotope labeling with data-dependent mass spectrometry, we have confirmed the accumulation of glycolipids (GM1 and GA1) and N-linked glycans with terminal beta-linked galactose. We have also discovered a novel set of core 1 and 2 O-linked glycan metabolites, many of which are part of structurally-related isobaric series that accumulate in disease. In the brain of GLB1 null mice, the levels of these glycan metabolites increased along with those of both GM1 and GA1 as a function of age. In addition to brain tissue, we found elevated levels of both N-linked and O-linked glycan metabolites in a number of peripheral tissues and in urine. Both brain and urine samples from human GM1 gangliosidosis patients exhibited large increases in steady state levels for the same glycan metabolites, demonstrating their correlation with this disease in humans as well. Conclusions:Our studies illustrate that GLB1 deficiency is not purely a ganglioside accumulation disorder, but instead a broad oligosaccharidosis that include representatives of many ?-linked galactose containing glycans and glycoconjugates including glycolipids, N-linked glycans, and various O-linked glycans. Accounting for all ?-galactosidase substrates that accumulate when this enzyme is deficient increases our understanding of this severe disorder by identifying metabolites that may drive certain aspects of the disease and may also serve as informative disease biomarkers to fully evaluate the efficacy of future therapies.

Dataset Information

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

Publications

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

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