title: 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.
authors.affiliation: Greenwood Genetic Center, Greenwood, SC 29646, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Boccuto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
authors.forename: Heather
authors.initials: H
authors.lastname: Flanagan-Steet
authors.forename: Chin-Fu
authors.initials: CF
authors.lastname: Chen
authors.forename: Xiang
authors.initials: X
authors.lastname: Fan
authors.forename: Frank
authors.initials: F
authors.lastname: Bartel
authors.forename: Marharyta
authors.initials: M
authors.lastname: Petukh
authors.forename: Ayla
authors.initials: A
authors.lastname: Pittman
authors.forename: Robert
authors.initials: R
authors.lastname: Saul
authors.forename: Alka
authors.initials: A
authors.lastname: Chaubey
authors.forename: Emil
authors.initials: E
authors.lastname: Alexov
authors.forename: Michael
authors.initials: M
authors.lastname: Tiemeyer
authors.forename: Richard
authors.initials: R
authors.lastname: Steet
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002889:Chromosomes, Human, Pair 2; D017124:Conserved Sequence; D004625:Embryo, Nonmammalian / Q000378:metabolism; D059472:Exome; D005260:Female; D005679:G(M3) Ganglioside / Q000096:biosynthesis*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D006017:Glycolipids / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020752:Neurocutaneous Syndromes / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012799:Sialyltransferases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology
chemical_list: D005679:G(M3) Ganglioside; D006017:Glycolipids; D006023:Glycoproteins; D012799:Sialyltransferases; C021343:haematoside synthetase
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