A novel frameshift pathogenic variant in ST3GAL5 causing salt and pepper developmental regression syndrome (SPDRS): A case report

Manoochehri, Jamal; Dastgheib, Seyed Alireza; Khamirani, Hossein Jafari; Mollaie, Maryam; Sharifi, Zahra; Zoghi, Sina; Tabei, Seyed Mohammad Bagher; Mohammadi, Sanaz; Dehghanian, Fatemeh; Farbod, Zahra; Dianatpour, Mehdi

doi:10.1038/s41439-021-00164-8

Cited by 5 publications

(1 citation statement)

References 14 publications

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“…14 Additional variants in other populations have now been reported, including missense variants within conserved motifs of the GM3 synthase enzyme (Figure 1). 2,12,[15][16][17][18][19][20] These motifs represent conserved functional domains shared across the entire GT29 family of sialyltransferase enzymes. 21,22 Motif L is thought to contribute to donor substrate binding whereas motif S contains residues that are involved in the binding of both donor and acceptor substrates.…”

Section: Introductionmentioning

confidence: 99%

Compound heterozygous variants within two conserved sialyltransferase motifs of ST3GAL5 cause GM3 synthase deficiency

et al. 2022

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GM3 synthase deficiency (GM3SD) is caused by biallelic variants in ST3GAL5. The ganglioside GM3, enriched in neuronal tissues, is a component of lipid rafts and regulates numerous signaling pathways. Affected individuals with GM3SD exhibit global developmental delay, progressive microcephaly, and dyskinetic movements. Hearing loss and altered skin pigmentation are also common. Most of the reported variants in ST3GAL5 are found in motifs conserved across all sialyltransferases within the GT29 family of enzymes. These motifs include motif L and motif S which contain amino acids responsible for substrate binding. These loss-of-function variants cause greatly reduced biosynthesis of GM3 and gangliosides derived from GM3. Here we describe an affected female with typical GM3SD features bearing two novel variants that reside in the other two conserved sialyltransferase motifs (motif 3 and motif VS). These missense alterations occur in amino acid residues that are strictly invariant across the entire GT29 family of sialyltransferases. The functional significance of these variants was confirmed by mass spectrometric analysis of plasma glycolipids, demonstrating a striking loss of GM3 and accumulation of lactosylceramide and Gb3 in the patient. The glycolipid profile changes were accompanied by an increase in ceramide chain length on LacCer. No changes in receptor tyrosine phosphorylation were observed in patient-derived lymphoblasts, indicating that GM3 synthase loss-of-function in this cell type does not impact receptor tyrosine kinase activity. These findings demonstrate the high prevalence of loss-of-function ST3GAL5 variants within highly conserved sialyltransferase motifs in affected individuals with GM3SD.

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Section: Introductionmentioning

confidence: 99%

Compound heterozygous variants within two conserved sialyltransferase motifs of ST3GAL5 cause GM3 synthase deficiency

et al. 2022

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Epidemiology of congenital disorders of glycosylation (CDG)—overview and perspectives

et al. 2022

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Background and aim Congenital disorders of glycosylation (CDG) are a large heterogeneous group of about 170 rare inherited metabolic disorders due to defective protein and lipid glycosylation. This study aimed to assemble and summarise available data on the epidemiology of CDG. Methods A set of keywords related to epidemiology and CDG was defined. The keywords were combined through a custom Python script, search through the MEDLINE database, using PubMed as the search engine. The script retrieved the correspondent MEDLINE data from each article, and the relevant information was exported. Next, inclusion and exclusion criteria were set and applied during the selection phase. Finally, epidemiology-related information was extracted and compiled. Results One hundred sixty-five papers on CDG epidemiology were included in this literature review. Most of them reported on the frequency of symptoms in CDG patients followed in cohort studies, on pathogenic variant allelic frequency, and on the prevalence of the disorder in populations. According to this review, the most reported CDG was phosphomannomutase-2 deficiency (PMM2-CDG) followed in descending order by FKTN-CDG, EXT1/EXT2-CDG, ALG6-CDG, and PIGA-CDG. Conclusions We provide an overview on epidemiological data regarding 93 CDG by compiling information from the literature. Generating epidemiological data on CDG is important to appropriately target resources for CDG research and drug development and to support public health decision-making.

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Structure and function of mammalian sphingolipids in health and disease

Rabionet,

Engel,

Sandhoff

2023

Cellular Lipid in Health and Disease

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A novel frameshift pathogenic variant in ST3GAL5 causing salt and pepper developmental regression syndrome (SPDRS): A case report

Cited by 5 publications

References 14 publications

Compound heterozygous variants within two conserved sialyltransferase motifs of ST3GAL5 cause GM3 synthase deficiency

Compound heterozygous variants within two conserved sialyltransferase motifs of ST3GAL5 cause GM3 synthase deficiency

Epidemiology of congenital disorders of glycosylation (CDG)—overview and perspectives

Structure and function of mammalian sphingolipids in health and disease

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