GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings

Abstract

GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes showed that all the amino acid replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease.

Figure 1. GLB1 sequence alignments between species

Family 35 glycosyl hydrolases and related proteins were aligned in the regions surrounding the new amino acid changes (p.I51N, p.L69P, p.R109W, p.R148H, p.W161G, and p.S191N) identified in GM1 gangliosidosis patients. Both aligned amino acids are indicated by squares. * Total sequence homology; : Very high homology;. High homology. A. p.I51 and p.L69 amino acids; B. p.R109 amino acid; C. p.R148 and p.W161 amino acids; D. p.S191 amino acid.

Figure 2. Structural model of representatitive human GLB1 three- dimensional protein

Homology model of human GLB1 based upon two crystal structures, one from Penicillium and one from Bacteriodes, is presented. The structure was plotted and the amino acid substitutions p.I51N, p.R68W, p.L69P, p.R109W, p.R148H, p.W161G, and p.S191N were highlighted in the molecular graphic. The selected amino acids are in yellow and the galactose ligand in white, with the protein painted from NH2- starting to COOH- terminal with blue to red colours.