Faculty Collaboration Database

A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation. Hum Mol Genet 2014 Jan 15;23(2):418-33

Date

09/13/2013

Pubmed ID

24026681

Pubmed Central ID

PMC3869362

DOI

10.1093/hmg/ddt434

Scopus ID

2-s2.0-84892639259 (requires institutional sign-in at Scopus site)   130 Citations

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.

Author List

Boccuto L, Aoki K, Flanagan-Steet H, Chen CF, Fan X, Bartel F, Petukh M, Pittman A, Saul R, Chaubey A, Alexov E, Tiemeyer M, Steet R, Schwartz CE

Author

Kazuhiro Aoki PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Apoptosis
Chromosomes, Human, Pair 2
Conserved Sequence
Embryo, Nonmammalian
Exome
Female
G(M3) Ganglioside
Gene Expression Profiling
Gene Expression Regulation
Gene Knockdown Techniques
Genetic Variation
Glycolipids
Glycoproteins
Glycosylation
Humans
Male
Molecular Sequence Data
Neurocutaneous Syndromes
Neurons
Pedigree
Polymorphism, Single Nucleotide
Sialyltransferases
Zebrafish