In a Japanese patient with Fabry disease following an atypical clinical course characterized by late-onset cardiac involvement and significant residual GLA (see 301500), Sakuraba et al. (1990) identified a G-to-A transition in exon 6 of the GLA gene, resulting in an arg301-to-gln (R301Q) substitution.
Sawada et al. (1996) identified the R301Q substitution in a 45-year-old man who developed moderate proteinuria and was found to have the renal histologic findings of Fabry disease, together with a decrease in activity of alpha-galactosidase A in his plasma, urine, leukocytes, and skin fibroblasts. The mutation was inherited from his mother. The patient was unique in that he demonstrated only renal manifestations, whereas all other patients with atypical Fabry disease, including a case with the identical point mutation (Sakuraba et al., 1990), presented with cardiomyopathy.
Kase et al. (2000) characterized this mutant and another, Q279E (300644.0008), in a patient with the cardiac variant of Fabry disease. In contrast to patients with classic Fabry disease, who have no detectable alpha-galactosidase activity, patients with these variants have residual enzyme activity. Compared to normal control cells, fibroblasts from a patient with the Q279E mutation secreted only small amounts of alpha-galactosidase. The authors concluded that these 2 substitutions do not significantly affect enzymatic activity, but the mutant protein levels are decreased presumably in the endoplasmic reticulum of cells.
