A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation

Abstract

'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 four 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.E332K) 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 (GSL) degradation, very little is known regarding the molecular and pathophysiologic consequences of altered GSL 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 GSL biosynthetic pathways. Comprehensive glycomic analysis of N-linked, O-linked and GSL 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 GSL expression in normal neural development and function.

Ganglioside Regulation of AMPA Receptor Trafficking

“…Congenital, refractory early onset seizures accompanied by profound psychomotor delay were traced to mutations in ST3GAL5 (Fig. 1), which codes for GM3 synthase, a sialyltransferase that acts early in the complex ganglioside biosynthetic pathway (Simpson et al, 2004;Fragaki et al, 2013;Boccuto et al, 2014). Hereditary spastic paraplegia associated with intellectual disability and occasional seizure susceptibility was traced to B4GALNT1, which codes for GM2/GD2 synthase, a subsequent step in ganglioside biosynthesis (Wilkinson et al, 2005;Boukhris et al, 2013;Harlalka et al, 2013).…”

GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome‐like phenotype

“…The protein from the nonsense mutation, c.862C>T, was truncated between L-and S-motifs, which has been reported in Old Order Amish patients [Simpson et al, 2004;Fragaki et al, 2013;Wang et al, 2013]. The other mutation, c.994G>A in an African-American family, was within the S-motif, which might result in disturbed function of S-motif, interacting with the lactosylceramide acceptor and a sugar donor [Boccuto et al, 2014]. Compared with the cases with the two mutations reported previously, the two sisters in the present study had neither epilepsy nor blindness.…”

“…This condition resulting from the impaired ganglioside biosynthesis pathway can disturb neurodevelopment, which clinically manifest with severe developmental delay/intellectual disability and epilepsy during infancy [Simpson et al, 2004;Fragaki et al, 2013;Wang et al, 2013;Boccuto et al, 2014]. The disease may also present with irritability during early infancy, failure to thrive, cutaneous dyspigmentation, blindness, and deafness [Simpson et al, 2004;Farukhi et al, 2006;Inokuchi, 2011;Fragaki et al, 2013;Wang et al, 2013;Boccuto et al, 2014].…”

“…Diseases from the impaired ganglioside catabolism pathway are widely known, such as the lysosomal storage diseases [Kacher and Futerman, 2006]. However, only a few reports of diseases resulting from disturbance of the ganglioside biosynthesis pathway have been published to date [Simpson et al, 2004;Fragaki et al, 2013;Wang et al, 2013;Boccuto et al, 2014].…”

“…It is characterized clinically by infantile-onset epilepsy, severe intellectual disability, irritability, failure to thrive, blindness, choreoathetosis, and cutaneous dyspigmentation [Simpson et al, 2004;Fragaki et al, 2013;Boccuto et al, 2014].…”