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

Abstract

Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid is impaired in lysosomal membranes from Salla and ISSD patients. The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14-q15 in a linkage study using Finnish families. Salla disease and ISSD were further shown to be allelic disorders. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.

Infantile Sialic Acid Storage Disease: Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation

“…Previous reports have described SLC17A5 mutations in Finnish, Swedish, Danish, Italian, French, Polish, Yugoslav, Turkish, Bedouin, Japanese, and North American (including French Canadian) patients (Biancheri et al 2002(Biancheri et al , 2005Coker et al 2009;Erikson et al 2002;Landau et al 2004;Nakano et al 1996;Sonderby Christensen et al 2003;Tylki-Szymanska et al 2003;Verheijen et al 1999). Apart from the common p.Arg39Cys allele, no other founder alleles have been described.…”

“…Defects of the sialic acid transporter SLC17A5 cause a lysosomal storage disease characterized by systemic accumulation of free sialic acid in a wide range of tissues (Verheijen et al 1999). SLC17A5-related conditions include infantile sialic acid storage disease (ISSD; OMIM #269920, a lethal multisystem disorder), Salla disease (OMIM #604369, a slowly progressive, predominantly neurological condition), and intermediate phenotypes (Aula et al 2000;Verheijen et al 1999).…”

“…SLC17A5-related conditions include infantile sialic acid storage disease (ISSD; OMIM #269920, a lethal multisystem disorder), Salla disease (OMIM #604369, a slowly progressive, predominantly neurological condition), and intermediate phenotypes (Aula et al 2000;Verheijen et al 1999). Recently, SLC17A5 mutations have also been identified in children and adults with cerebral palsy-like chronic encephalopathy; thus, the recognized spectrum of clinical phenotypes continues to expand (Debray et al 2011;Mochel et al 2009Mochel et al , 2010.…”

“…A majority of ISSD cases demonstrate fetal hydrops and/or ascites; hence, this can be considered a prenatal-onset condition (Froissart et al 2005). General genotype-phenotype correspondences have been established, and (with exceptions) most Salla disease patients have at least one copy of the common Finnish founder allele, p.Arg39Cys (NM_012434.4:c.115C>T) bearing some residual transporter activity in vitro (Aula et al 2000;Morin et al 2004;Verheijen et al 1999;Wreden et al 2005;Mochel et al 2009). In contrast, a wide range of mutation types are seen in ISSD; those studied in vitro appear to be functionally null (Aula et al 2000;Morin et al 2004;Myall et al 2007;Ruivo et al 2008;Wreden et al 2005).…”

Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity

“…Individuals with symptoms of moderate severity are considered to have "intermediate severe Salla disease." There is a correlation between the phenotypes of these three groups of patients and their genetic mutations in SLC17A5, the gene that codes for the lysosomal sialic acid transporter, sialin [3][4][5][6][7][8][9]. The diVerential diagnosis of free sialic acid storage also includes sialuria, due to defective feedback inhibition of UDP-GlcNAc-2-epimerase by CMP-sialic acid in the sialic acid synthetic pathway [10].…”