Three novel beta-galactosidase gene mutations in Han Chinese patients with GM1 gangliosidosis are correlated with disease severity

Abstract

BackgroundGM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease caused by deficiency of acid beta-galactosidase (GLB1; EC3.2.1.23). Here, we identify three novel mutations in the GLB1 gene from two Han Chinese patients with GM1 that appear correlated with clinical phenotype.MethodsOne of the two Han Chinese patients with GM1 presented with the juvenile form, and the other with the infantile form with cardiac involvement. Sequencing of the entire GLB1 gene revealed three novel mutations (p.H102 D, p.G494V, c.495_497delTCT), which were absent in 94 normal controls. Transient expression of cDNA encoding these variants was performed in COS-1 cells to evaluate β-galactosidase activities.ResultsThe first case (patient 1) with the juvenile form contained two missense mutations, p.H102 D and p.A301V. Patient 2 diagnosed with the infantile form of the disease with cardiac involvement was compound heterozygous for p.G494V and c.495_497delTCT mutations. All mutant beta-galactosidases exhibited significantly reduced activity (12%, 0%, 0%, and 0% for p.H102 D, p.A301V, p.G494V, and c.495_497delTCT), compared with the wild-type beta-galactosidase cDNA clone. The mutations identified in patient 2 with cardiomyopathy were localized in the GLB1 gene region common to both lysosomal beta-galactosidase and elastin binding protein (EBP), and caused a deletion in the elastin-binding domain of EBP.ConclusionsAll four mutations identified in Han Chinese patients induce significant suppression of β-galactosidase activity, correlating with severity of disease and presence of cardiomyopathy.

Disentangling molecular and clinical stratification patterns in beta-galactosidase deficiency

“…Forty-seven variations were identified in GLB1 gene sequence (NM_000404.3). Twenty-nine variants have been previously published [6][7][8][9][10][11][12][13][14][15][16][17][18][19] and 18 are novel (Supplementary tables S4 and S5). The novel variants include 15 missense variants and 3 deletions, their frequencies were evaluated using gnomAD.…”

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing GM1‐gangliosidosis and Morquio B disease

“…Only a few of the 140 mutations of the GLB1 gene (Brunetti-Pierri and Scaglia 2008;Hofer et al 2009;Hofer et al 2010;Yang et al 2010) have so far sufficiently been explored for structure and metabolism of resultant enzyme precursors. We recently characterized the GLB1 gene products from mono-and heteroallelic GM1 cases by expression in COS-1 cells, Western blotting, and immunolocalization (Hofer et al 2009;Hofer et al 2010) and identified novel chaperone-responsive GM1 alleles (p.C230R, p.G438E) besides previously known sensitive alleles (p.R201C, p.R201H) by a new lipophilic derivative of 1-deoxygalactonojirimycin, DLHex-DGJ (Methyl 6-{[N 2 -(dansyl)-N 6 -(1,5-dideoxy-D-galactitol-1,5-diyl)-L-lysyl] amino} hexanoate) Steiner et al 2008).…”

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

“…The mechanism whereby p.Asn490del impacts GLB1 enzymatic function is unknown. Other similar in-frame deletions in GLB1 have been reported; however, they fall in other regions of the protein (Caciotti et al, 2011;Santamaria, Blanco, Chabás, Grinberg, & Vilageliu, 2007;Yang, Wu, & Tsai, 2010). In order to determine the effects of this mutation, we performed molecular dynamics simulations comparing the mutant and wild-type (WT) protein.…”

“…Oral aversion requiring gastrostomy has been reported in infants having gastroschisis (Overcash et al., ). Use of gastrostomy to combat dysphagia and prevent aspiration resulting from GM1/GM2 gangliosidosis is also a common practice (Jarnes Utz et al., ).…”