ClinVar Genomic variation as it relates to human health

In 8 families of Australian/English, Australian/Scottish, English, or Canadian extraction with hereditary sensory neuropathy type IA (HSAN1A; 162400), Dawkins et al. (2001) identified a heterozygous c.399T-G transversion in exon 5 of the SPTLC1 gene, resulting in a cysteine-to-tryptophan substitution at codon 133 (C133W). Cysteine-133 of SPTLC1 is invariant in human, mouse, Drosophila, and yeast. In a family of Canadian origin, Bejaoui et al. (2001) independently identified this mutation. Nicholson et al. (2001) performed haplotype analysis on 3 Australian families of English extraction and 3 English families (2 of which had been described elsewhere) with the cys133-to-trp mutation and demonstrated the same chromosome 9 haplotype as well as the same phenotype in all. They suggested that these families may have had a common founder who, on the basis of historical information, lived in southern England before 1800. The phenotype caused by the 399T-G SPTLC1 mutation is the same as that in the families reported by Campbell and Hoffman (1964) and possibly the original family reported by Hicks (1922), all of which were English. In Chinese hamster ovary (CHO) cells and yeast, Gable et al. (2010) demonstrated that the C133W-mutant protein was expressed and formed a stable heterodimer with SPTLC2 (605713), but did not confer catalytic SPT activity even when cotransfected with wildtype SPTLC1, thus showing a dominant-negative effect. Coexpression of the mutant protein with the catalytic enhancers SSSPTB (610412) and SSSPTA (613540) provided sufficient SPT activity to support growth in yeast, although total enzyme activity was only 10 to 20% of wildtype. Yeast and CHO cells expressing the C133W mutant along with SPTLC2 and SSSPTA or SSSPTB showed preferential condensation of palmitoyl-CoA to alanine rather than serine. These results were not found with wildtype SPTLC1. Kinetic studies showed that the mutant protein had the same affinity to serine as the wildtype protein, but a lower Vmax for serine. These findings suggest that the C133W mutation perturbs the active site of the protein, facilitating the formation of alanine condensation products. However, small increases in extracellular serine levels were able to inhibit the reaction with alanine. The palmitoyl-CoA/alanine product, 1-deoxysphinganine (1-deoxySa), was shown to increase endoplasmic reticulum stress and the unfolded protein response, which may ultimately be toxic to neurons. (less)