The potential consequences of bidirectional promoter methylation on and expression in Fabry disease phenotypes in a family of patients carrying a deletion variant.

Fabry disease (FD) is a rare inherited disease characterized by a wide range of symptoms attributed to mutations resulting in defective α-galactosidase A (α-Gal A) and accumulation of glycosphingolipids. The locus is paired in a divergent manner with the heterogeneous nuclear ribonucleoprotein locus mapped in the readthrough locus. As a follow-up to our recent finding of the co-regulation of and via a bidirectional promoter (BDP) in normal kidney and skin cells, the potential accumulative influence of BDP methylation and mutation on the severity of FD in patients from the same family, two males and two females carrying a deletion mutation, c.1033_1034delTC (p.Ser345Argfs) was addressed in the present study. The molecular analyses of the FD patients compared with the control revealed that the expression of was significantly low (P<0.05), and showed a tendency of low expression (P=0.1) when BDP methylation was elevated in FD patients, compared with low BDP methylation and high expression (P<0.05), and a high trend of expression in normal individuals. The accumulative effects of the mutation and BDP methylation with the severity of the disease were observed in three patients. One male FD patient, a member of the FD family diagnosed with progressive loss of kidney function, hypertension, and eventually a stroke, and the lowest level of α-Gal A enzyme activity showed the highest BDP DNA methylation level. It is concluded that the DNA methylation of - BDP may serve a role in diagnosing and treating FD.