Unraveling the molecular pathogenesis of free sialic acid storage disorders: altered targeting of mutant sialin.

Salla disease (SD) and infantile sialic acid storage disease (ISSD) are recessively inherited, neuro-degenerative disorders caused by mutations in the SLC17A5 gene. The gene product, sialin, is a lysosomal membrane protein which transports free sialic acid across the membrane. Although the function of sialin is basically known, the details of biosynthesis and intracellular trafficking as well as functional consequences of disease mutations in the SLC17A5 gene are not characterized. Here we studied for the first time the expression, localization, and targeting of the wild-type sialin as well as two mutant polypeptides; one mimicking the Finnish founder mutation, R39C (Salla(FIN)), and the other a deletion (del268-272) found in ISSD patients using in vitro expression of the corresponding cDNA constructs. The wild-type sialin was targeted to lysosomes whereas a significant fraction of the Salla(FIN) polypeptides and the majority of the ISSD polypeptides remained in the Golgi compartment. Further, using a temperature block of intracellular transport, we observed that the rate of the trafficking of the mutant polypeptides to lysosomes is significantly slower than that of their wild-type counterpart. These findings are in line with the phenotypic differences between SD and ISSD, the former presenting mental retardation with long life span in contrast to the latter being an early fatal disorder.