ArticleBrain : a journal of neurology2023
SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia.
Article in Brain : a journal of neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 25 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
25 citing papers in PubMed, 33 citations in OpenAlex.
- Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease.Brain : a journal of neurology · 2026Article
- Characterization of novel and recurrentJournal of neuromuscular diseases · 2026Article
- Rigorous genetic diagnosis review in natural history studies.Orphanet journal of rare diseases · 2026Article
- Integrated transcriptomic and tissue-validation analyses identify palmitoylation-associated biomarkers linked to sphingolipid metabolism and immune remodeling in psoriasis.Frontiers in immunology · 2026Article
- Neurogenetic Disorders with Hearing Loss: Mechanisms, Classifications, and Emerging Insights.Current neurology and neuroscience reports · 2025Review
- Characterization of SPTLC2 as a key driver promoting microglial activation and energy metabolism reprogramming after ischemic stroke through bulk and single-cell analyses combined with experimental validation.Cell biology and toxicology · 2025Article
- The individual isoforms of ORMDL, the regulatory subunit of serine palmitoyltransferase, have distinctive sensitivities to ceramide.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2025Article
- Intricate Regulation of Sphingolipid Biosynthesis: An In-Depth Look Into ORMDL-Mediated Regulation of Serine Palmitoyltransferase.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- Article
- SPTSSA facilitates gastric cancer progression with modulating PD-L1 in immunomicroenvironment through Wnt/β-catenin pathway.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Functional assays inGenome research · 2025Review
- The bioactive sphingolipid playbook. A primer for the uninitiated as well as sphingolipidologists.Journal of lipid research · 2025Review
- Human genetic defects of sphingolipid synthesis.Journal of inherited metabolic disease · 2025Review
- Identification of key genes associated with idiopathic pulmonary fibrosis and sarcopenia by bioinformatics analysis.PloS one · 2025Article
- SPTLC3 regulates plasma membrane sphingolipid composition to facilitate hepatic gluconeogenesis.Cell reports · 2024Article
- Regulation of cellular and systemic sphingolipid homeostasis.Nature reviews. Molecular cell biology · 2024Review
- SPTLC2 variants are associated with early-onset ALS and FTD due to aberrant sphingolipid synthesis.Annals of clinical and translational neurology · 2024Article
- RecurrentJournal of neurology, neurosurgery, and psychiatry · 2024Article
- Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.Journal of neuromuscular diseases · 2024Review
- Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans.Nature reviews. Genetics · 2024Review
Corrections and comments
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Authors and funding
27 authors at 9 institutions in 2 countries.
Funding
Abstract
Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila. Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila. These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.