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. 2000 Oct;67(4):832-40.
doi: 10.1086/303077. Epub 2000 Aug 17.

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

N Aula  1 , P Salomäki, R Timonen, F Verheijen, G Mancini, J E Månsson, P Aula, L Peltonen
Affiliations

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

N Aula et al. Am J Hum Genet. 2000 Oct.

Abstract

Lysosomal free sialic acid-storage diseases include the allelic disorders Salla disease (SD) and infantile sialic acid-storage disease (ISSD). The defective 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 with either Salla disease or the ISSD phenotype. We also report for the first time the exon-intron boundaries of SLC17A5. All Finnish patients with SD (n=80) had a missense mutation changing a highly conserved arginine to cysteine (R39C); 91% of them were homozygotes for this old founder mutation. The compound-heterozygote patients, with the founder mutation in only one allele, presented with a more severe phenotype than did the homozygote patients. The same R39C mutation was also found both in most of the Swedish patients with SD and in a heterozygous form in five patients from central Europe who presented with an unusually severe (intermediate) SD phenotype. Ten different mutations, including deletions, insertions, and missense and nonsense mutations, were identified in patients with the most severe ISSD phenotype, most of whom were compound heterozygotes. Our results indicate some genotype-phenotype correlation in free sialic acid-storage diseases, suggesting that the phenotype associated with the homozygote R39C mutation is milder than that associated with other mutations.

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Figures

Figure 1
Figure 1
A, Sialin mutations in patients with free SASD shown in the predicted model of sialin in the lysosomal membrane are denoted in terms of amino acid position. Only the start points of deletions and insertions are indicated. SSLRN = in-frame deletion of Ser, Ser, Leu, Arg, and Asn. B, SLC17A5 mutations in patients with free SASD. Point mutations are marked with an arrow (↓), deletion points with an upside-down triangle (▿), and insertion points with a triangle (▵).
Figure 2
Figure 2
Expression of SLC17A5 in patients with classical SD, severe SD, and ISSD. A northern blot made from total RNAs was hybridized with a 32P-labeled 140-bp PCR probe amplified from SLC17A5 cDNA and subsequently rehybridized with 32P-labeled β-actin, to evaluate the loading of the samples.
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References

Electronic-Database Information

    1. BLAST, http://www.ncbi.nlm.nih.gov/BLAST
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/omim (for SASD [MIM 269920]) - PubMed

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