A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases

Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neu rodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland(1,2) (Sa lla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infanti le cases(3). Progressive cerebellar atrophy and dysmyelination have been do cumented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are see n on electron microscopic studies and patients excrete large amounts of fre e sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic a cid and glucuronic acid(5) is impaired in lysosomal membranes from Salla an d ISSD patients(6). The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14-q15 in a linkage study using Finni sh families(7,8). Salla disease and ISSD were further shown to be allelic d isorders(9). A physical map with PZ and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basi s for precise physical positioning of the gene(10). Here we describe a new gene, SLC17A5(also known as AST), encoding a protein (sialin) with a predic ted transport function that belongs to a family of anion/cation symporters (ACS). Mle found a homozygous SLC17A5 mutation (R39C) in five Finnish patie nts with Salla disease and six different SLC17A5 mutations in six ISSD pati ents of different ethnic origins. Our observations suggest that mutations i n SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.