Boccuto, L., Aoki, K., Flanagan-Steet, H., Chen, C.F., Fan, X., Bartel, F., Petukh, M., Pittman, A., Saul, R., Chaubey, A., Alexov, E., Tiemeyer, M., Steet, R., and Schwartz, C.E. (2014) A Mutation in a Ganglioside Biosynthetic Enzyme, ST3GAL5, Results in Salt & Pepper Syndrome, a Neurocutaneous Disorder with Altered Glycolipid and Glycoprotein Glycosylation. Human molecular genetics. 23(2):418-33.
“Salt & Pepper” syndrome is an autosomal recessive condition characterized by severe intellectual disability, epilepsy, scoliosis,
choreoathetosis, dysmorphic facial features, and altered dermal pigmentation. High density SNP array analysis performed on
siblings first described with this syndrome detected 4 shared regions of loss of heterozygosity (LOH). Whole-exome sequencing
narrowed the candidate region to chromosome 2p11.2. Sanger sequencing confirmed a homozygous c.994G>A transition (p.E332 K)
in the ST3GAL5 gene, which encodes for a sialyltransferase also known as GM3 synthase. A different homozygous mutation of this gene has
been previously associated with infantile-onset epilepsy syndromes in two other cohorts. The ST3GAL5 enzyme synthesizes ganglioside
GM3, a glycosophingolipid enriched in neural tissue, by adding sialic acid to lactosylceramide. Unlike disorders of glycosphingolipid
degradation, very little is known regarding the molecular and pathophysiologic consequences of altered glycosphingolipid biosynthesis.
Glycolipid analysis confirmed a complete lack of GM3 ganglioside in patient fibroblasts, while microarray analysis of glycosyltransferase
mRNAs detected modestly increased expression of ST3GAL5 and greater changes in transcripts encoding enzymes that lie downstream of ST3GAL5 and in other glycosphingolipid biosynthetic
pathways. Comprehensive glycomic analysis of N-linked, O-linked, and glycosphingolipid glycans revealed collateral alterations
in response to loss of complex gangliosides in patient fibroblasts and in zebrafish embryos injected with antisense morpholinos
that targeted zebrafish st3gal5 expression. Morphant zebrafish embryos also exhibited increased apoptotic cell death in multiple brain regions, emphasizing
the importance of glycosphingolipid expression for normal neural development and function.