Human genetic disorders of sphingolipid biosynthesis

Astudillo, L.; Sabourdy, Frédérique; Therville, Nicole; Bode, Heiko; Ségui, Bruno; Hornemann, Thorsten; Levade, Thierry

doi:10.1007/s10545-014-9736-1

Cited by 28 publications

(16 citation statements)

References 106 publications

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“…Defects in the synthesis pathway are also associated with disease. Mutations in SPT (SPTLC1 and SPTLC2) lead to the formation of aberrant and neurotoxic 1-deoxysphingolipids, which result in hereditary sensory and autonomic neuropathy type I (OMIM #162400, #613640) (12). Genetic variants in ceramide synthase 1 and 2 (CERS1/2) are associated with progressive myoclonic epilepsy, generalized tonic-clonic seizures, tremor, dysarthria, ataxia, and developmental delay (OMIM #616230) (13)(14)(15).…”

Section: Resultsmentioning

confidence: 99%

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans

Karsai

Kraft

Haag

et al. 2019

Journal of Clinical Investigation

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102

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Volume 129 Number 3 March 2019 conjugation of L-serine and palmitoyl-CoA, the rate-limiting step catalyzed by serine palmitoyltransferase (SPT). The immediate product 3-keto-sphinganine is reduced to sphinganine (SA), which is then N-acylated to dihydroceramide (dhCer) by 1 of 6 ceramide synthase isoforms (CerS1-6) (4). In the final step, dhCer is converted to ceramide by the insertion of a Δ4,5 trans (Δ4E) double bond into the SA backbone. This final conversion is catalyzed by the Δ4-dihydroceramide desaturase DEGS1 (5). On the catabolic side, ceramides are deacylated by ceramidases to form sphingosine (SO), which can be either recycled back to ceramides (sal-BACKGROUND. Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive. METHODS.A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder. RESULTS.By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1. CONCLUSION.We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems.(OMIM #617575) (19-21), but also with axonal peripheral neuropathy without renal or adrenal deficiencies (22).Here, we identify DEGS1 dysfunction as the cause of an SL disorder with leukodystrophy and hypomyelination of the peripheral nervous system.

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Section: Resultsmentioning

confidence: 99%

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans

Karsai

Kraft

Haag

et al. 2019

Journal of Clinical Investigation

Self Cite

102

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“…More recently, mutations in GBA2 were identified in ARCA patients presenting with additional spasticity and/or cataracts (Martin et al, 2013). Unlike GBA1, GBA2 is mostly expressed in the ER and may constitute an alternative pathway to produce ceramide outside the lysosome (Astudillo et al, 2015).…”

Section: Lipid Metabolism In Arcasmentioning

confidence: 99%

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Synofzik

Puccio

Mochel

et al. 2019

Neuron

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Autosomal-recessive cerebellar ataxias (ARCAs) comprise a heterogeneous group of rare degenerative and metabolic genetic diseases that share the hallmark of progressive damage of the cerebellum and its associated tracts. This Review focuses on recent translational research in ARCAs and illustrates the steps from genetic characterization to preclinical and clinical trials. The emerging common pathways underlying ARCAs include three main clusters: mitochondrial dysfunction, impaired DNA repair, and complex lipid homeostasis. Novel ARCA treatments might target common hubs in pathogenesis by modulation of gene expression, stem cell transplantation, viral gene transfer, or interventions in faulty pathways. All these translational steps are addressed in current ARCA research, leading to the expectation that novel treatments for ARCAs will be reached in the next decade.

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“…These sphingolipid mediators and their enzymes regulate aspects of cellular and tissue homeostasis, such as the cell cycle, senescence, proliferation, migration, immune response, and inflammation 20-22 . In the CNS, these mediators are highly enriched in the brain, where they are pivotal components of cell membranes and play an essential role in proper brain development and function [23][24][25] . Defects in sphingolipid metabolism result in disturbances in membrane organization, suppression of cell growth and promotion of apoptosis in different cell types, including neurons [24][25][26][27] . Acid sphingomyelinase (ASM), which is encoded by the Smpd1 gene, is one of the significant sphingolipidmetabolizing enzymes 28 .…”

Section: Introductionmentioning

confidence: 99%

Potential therapeutic target for aging and age-related neurodegenerative diseases: the role of acid sphingomyelinase

2020

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Aging, which is associated with age-related changes in physiological processes, is the most significant risk factor for the development and progression of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Accumulating evidence has indicated that sphingolipids are significant regulators that are associated with pathogenesis in aging and several age-related neurodegenerative diseases. In particular, abnormal levels of acid sphingomyelinase (ASM), one of the significant sphingolipid-metabolizing enzymes, have been found in the blood and some tissues under various neuropathological conditions. Moreover, recent studies have reported the importance of ASM as a critical mediator that contributes to pathologies in aging and age-related neurodegenerative diseases. In this review, we describe the pathophysiological processes that are regulated by ASM, focusing on the age-related neurodegenerative environment. Furthermore, we discuss novel insights into how new therapeutics targeting ASM may potentially lead to effective strategies to combat aging and age-related neurodegenerative diseases.

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Human genetic disorders of sphingolipid biosynthesis

Cited by 28 publications

References 106 publications

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Potential therapeutic target for aging and age-related neurodegenerative diseases: the role of acid sphingomyelinase

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