GM1 Gangliosidosis-A Mini-Review

Abstract

GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the GLB1 gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms [Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult)], based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the GLB1 gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the Glb1 murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three GLB1 gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).

Keywords: GM1 gangliosidosis; beta galactosidase; gene therapy; glycoconjugates metabolism; mouse model.

Conflict of interest statement

Ad’A holds the Jewelers for Children Endowed Chair in Genetics and Gene Therapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Nicoli, Annunziata, d’Azzo, Platt, Tifft and Stepien.

Figures

FIGURE 1

Pathogenesis and clinical manifestations. Panel 1: human β-GAL is composed of a catalytic TIM barrel domain followed by β-domain 1 and β-domain 2 (Ohto et al., 2012). Mutations in the GLB1 gene lead to impaired enzyme activity, which results in the progressive accumulation of complex gangliosides, specifically GM1. This, in turn, initiates a series of pathogenic events that ultimately lead to neurodegeneration (Kolter, 2012; Annunziata et al., 2018). Panel 2: through alternative splicing, the GLB1 gene gives rise to two transcripts, one encoding the hydrolytic enzyme β-galactosidase and the other the elastin binding protein (EBP). The primary role of EBP is to chaperone the deposition of elastin fibers in the extracellular matrix (ECM). β-galactosidase (GLB1) and EBP are found in complex with PPCA and NEU1 in lysosomes and the plasma membrane (PM), respectively (Caciotti et al., 2005; Bonten et al., 2014). Panel 3: although GM1 gangliosidosis is a disease continuum it can be loosely divided into 3 types, with Type II having 2 subtypes. The common use of a synthetic fluorogenic substrate to measure β-GAL activity makes it difficult to establish an accurate correlation between residual enzyme activity and clinical outcome. This may also be complicated by the regulatory and post posttranslational mechanisms that influence GM1-ganglioside catabolism and may vary among patients (Breiden and Sandhoff, 2019). The main symptoms of the disease commonly found in each type/subtype are summarized.

FIGURE 2

Genotypes in GM1 gangliosidosis. Schematic representation of 261 GLB1 variants with a reported phenotype of GM1-gangliosidosis and/or Morquio B registered in the database HGMD (2021) updated with the novel variants from Tebani et al. (2021). The GLB1 gene is located on the short arm of chromosome 3 (3p21.33). GM1 gangliosidosis and Morquio B disease result from biallelic mutations in GLB1 gene. Mutations affecting the catalytical site of the β-GAL enzyme may reduce or eliminate the degradation of GM1 substrate. GLB1 cDNA sequence NM_000404.4; Ref SeqGene NG_009005.1; 194 Missense/Nonsense (dark blue), 20 Splicing substitutions (dark green), 25 small deletions (pink), 17 small insertion/duplications (light blue), 2 small indels (orange), 1 gross deletion (purple), 2 gross insertion/duplications (light green). Bold text represents GM1 gangliosidosis and/or Morquio B reported phenotypes. A summary of the 261 reported variants with a phenotype of GM1 gangliosidosis and/or Morquio B disease can be found at GLB1 (HGMD, 2021; Tebani et al., 2021). The main domains of the protein are shown above the exons. For a full description on the clinical pathogenicity of each variant the database ClinVar (Landrum et al., 2018) provides information about genomic variation and its relationship to human health at GLB1 (ClinVar, 2021).