The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation

Lysosomal free sialic acid-storage diseases include the allelic disorders S alla disease (SD) and infantile sialic acid-storage disease (ISSD). The def ective gene, SLC17A5, coding for the lysosomal free sialic acid transporter was recently isolated by positional cloning. In the present study, we have identified a large number of mutations in SLC17A5 in patients presenting w ith either Salla disease or the ISSD phenotype. We also report for the firs t time the exon-intron boundaries of SLC17A5. All Finnish patients with SD (n = 80) had a missense mutation changing a highly conserved arginine to cy steine (R39C); 91% of them were homozygotes for this old founder mutation. The compound-heterozygote patients, with the founder mutation in only one a llele, presented with a more severe phenotype than did the homozygote patie nts. The same R39C mutation was also found both in most of the Swedish pati ents with SD and in a heterozygous form in five patients from central Europ e who presented with an unusually severe (intermediate) SD phenotype. Ten d ifferent mutations, including deletions, insertions, and missense and nonse nse mutations, were identified in patients with the most severe ISSD phenot ype, most of whom were compound heterozygotes. Our results indicate some ge notype-phenotype correlation in free sialic acid-storage diseases, suggesti ng that the phenotype associated with the homozygote R39C mutation is milde r than that associated with other mutations.