Abstract
Missense mutations in the α-galactosidase A (GLA) gene comprising the majority of mutations responsible for Fabry disease result in heterogeneous phenotypes ranging from the early onset severe “classic” form to the “later-onset” milder form. To elucidate the molecular basis of Fabry disease from the viewpoint of structural biology, we comprehensively examined the effects of different substitutions at the same residue in the amino acid sequence of GLA on the structural change in the enzyme molecule and the clinical phenotype by calculating the number of atoms affected and the root-mean-square-distance value, and by coloring of the atoms influenced by the amino acid replacements. The results revealed that the severity of the structural change influences the disease progression, i.e., a small structural change tends to lead to the later-onset form and a large one to the classic form. Furthermore, the study revealed the residues important for expression of the GLA activity, i.e., residues involved in construction of the active site, a disulfide bond or a dimer. Structural study from such a viewpoint is useful for elucidating the basis of Fabry disease.
Highlights
Fabry disease (MIM 301500) is an X-linked genetic disorder resulting from a deficiency of a-galactosidase A (GLA; EC 3.2.1.22) activity [1]
We examined the numbers of affected atoms for the whole enzyme protein and for the active site, and the rootmean-square distance (RMSD) and accessible surface area (ASA) values
This suggests that the structural change resulting from the amino acid substitutions leading to the classic phenotype is essentially greater than that in the later-onset one, there are some exceptional cases, i.e., in R112H and R301Q, the numbers of affected atoms and the RMSD values are apparently large, the patients with these mutations exhibited the later-onset phenotype (Table 1)
Summary
Fabry disease (MIM 301500) is an X-linked genetic disorder resulting from a deficiency of a-galactosidase A (GLA; EC 3.2.1.22) activity [1]. The disease exhibits a wide range of clinical phenotypes, from the early-onset severe ‘‘classic’’ form to the ‘‘later-onset’’ milder one [2]. Male patients with the classic form of Fabry disease, who have little or no GLA activity, develop pain in the peripheral extremities, hypohidrosis, angiokeratomas and corneal opacities in childhood or adolescence, and manifest renal, cardiac, and cerebrovascular complications in the fourth to fifth decade of life [3]. Male patients with the later-onset form, who have residual GLA activity, develop heart and kidney disorders without the childhood symptoms [4]. Heterozygous Fabry females exhibit a wide spectrum of disease severity ranging from asymptomatic to presentation with the classic disease due to random X-chromosomal inactivation [5]
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