Fabry disease: correlation between structural changes in α-galactosidase, and clinical and biochemical phenotypes

Abstract

Fabry disease comprises classic and variant phenotypes. The former needs early enzyme replacement therapy, and galactose infusion is effective for some variant cases. Attempts of early diagnosis before manifestations appear will begin in the near future. However, it is difficult to predict the phenotype, to determine the therapeutic approach, only from genetic information. Thus we attempted structural analysis from a novel viewpoint. We built structural models of mutant alpha-galactosidases resulting from 161 missense mutations (147 classic and 14 variant), and evaluated the influence of each replacement on the structure by calculating the numbers of atoms affected. Among them, 11 mutants, biochemically characterized, were further investigated by color imaging of the influenced atoms. In the variant group, the number of atoms influenced by amino-acid replacement was small, especially in the main chain. In 85% of the cases, less than three atoms in the main chain are influenced. In this group, small structural changes, located apart from the active site, result in destabilization of the mutant enzymes, but galactose can stabilize them. Structural changes caused by classic Fabry mutations are generally large or are located in functionally important regions. In 82% of the cases, three atoms or more in the main chain are affected. The classic group comprises dysfunctional and unstable types, and galactose is not expected to stabilize the mutant enzymes. This study demonstrated the correlation of structural changes, and clinical and biochemical phenotypes. Structural investigation is useful for elucidating the bases of Fabry disease and clinical treatment.

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

“…[18][19][20][21][22] We defined that the structure was influenced by an amino acid substitution when the position of an atom in a mutant differed from that in the wild-type structure by more than the cut-off distance (0.15 Å ) on the basis of the total root-mean-square distance (RMSD), as described earlier. [18][19][20][21][22] The numbers of influenced atoms in the main chain and the side chain were calculated. Abbreviations: ASA, solvent-accessible surface area; RMSD, root-mean-square distance; À, no protein; ¼, normal amount; m, more than normal; k, less than normal.…”

Structural bases of GM1 gangliosidosis and Morquio B disease

“…Each mutant model was then superimposed on the wild-type structure based on the Ca atoms using the least-square-mean fitting method. 31,32 We reported that the structure was influenced by an amino-acid substitution when the position of an atom in a mutant differed from that in the wild type by more than the cutoff distance (0.15 Å ) on the basis of the total RMSD, as described previously. 32 We calculated the numbers of influenced atoms in both the main chain and the side chain.…”

“…The analysis was based on the differences between the wild types and mutants to determine the influence of the amino-acid substitutions geographically and semi-quantitatively according to the method described previously. 32 …”

Doença de Fabry

“…Por exemplo, diferentes mutações estão associadas a fenó-tipos similares, enquanto membros de uma família que compartilha a mesma mutação apresentam diferentes fenótipos. 7,13 Quando se suspeita do diagnóstico de DF, a pesquisa da história familiar é muito importante, já que a maioria dos casos ocorre de forma hereditária. Porém a ausência de dados familiares positivos não invalidam o diagnóstico, uma vez que mutaçoes têm sido documentadas.…”