Lysosomal storage disorders are marked by an accumulation of organic material within lysosome organelles due to defects either in the degradation of macromolecules within lysosomes or the transport of end products across the lysosomal membrane. Among such disorders are Salla disease and infantile sialic acid storage disease (ISSD), two autosomal recessive neurodegenerative diseases that result from mutations in a gene encoding the lysosomal sialic acid transporter, sialin [1
]. The more severe ISSD is typically characterized by neonatal ascites, intrauterine hydrops, dysmorphic features, and death by 2 years of age, but individuals with a less severe phenotype and longer life-spans have been described in the literature. On the other hand, individuals with Salla disease are noted to have cognitive and motor impairment as early as 6-12 months after birth, but typically reach adulthood.
Missense mutations throughout the predicted sialin sequence have been associated with the lysosomal free sialic acid storage disorders [2
]. Recently disease-associated mutations leading to substitutions of conserved glycines (G328E and G409E) have been identified (). The G328E mutation has been found as a homozygous mutation in four relatives in a single family [6
]. While one individual presented with congenital ascites and died shortly after birth, others were noted to have a milder phenotype with survival to at least several years of age. The G409E mutation has been identified in a compound heterozygous individual with a phenotype intermediate in severity between ISSD and Salla disease [7
]. The second mutation in this individual is predicted to lead to a splicing defect and a subsequent frame-shift leading to a truncated protein of 32 amino acids.
Figure 1 A) Comparison of the sequences corresponding to G328 and G409 and the surrounding residues in human, rat and drosophila sialin and human isoforms of two related proteins, VGLUT1 and NaPi1 demonstrate that these specific residues are completely conserved. (more ...)
To understand how these novel mutations might contribute to disease on a molecular level, we examined the transport activity and localization pattern of mutant recombinant sialin isoforms. Consistent with other disease-associated missense mutations, G328E and G409E mutations both lead to impairment of sialin mediated transport of free sialic acid. In addition the G409E also alters the localization of the protein. These results suggest that these residues may play a crucial role in proper folding and function of the protein, and thus add to our understanding of molecular pathology of the lysosomal free sialic acid storage disorders.