Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy

Abstract

Objective: To identify the unknown genetic cause in a nuclear family with an axonal form of peripheral neuropathy and atypical disease course.Methods: Detailed neurologic, electrophysiologic, and neuropathologic examinations of the patients were performed. Whole exome sequencing of both affected individuals was done. The effect of the identified sequence variations was investigated at cDNA and protein level in patient-derived lymphoblasts. The plasma sphingoid base profile was analyzed. Functional consequences of neuron-specific downregulation of the gene were studied in Drosophila.Results: Both patients present an atypical form of axonal peripheral neuropathy, characterized by acute or subacute onset and episodes of recurrent mononeuropathy. We identified compound heterozygous mutations cosegregating with disease and absent in controls in the SGPL1 gene, encoding sphingosine 1-phosphate lyase (SPL). The p.Ser361* mutation triggers nonsensemediated mRNA decay. The missense p.Ile184Thr mutation causes partial protein degradation. The plasma levels of sphingosine 1-phosphate and sphingosine/sphinganine ratio were increased in the patients. Neuron-specific downregulation of the Drosophila orthologue impaired the morphology of the neuromuscular junction and caused progressive degeneration of the chemosensory neurons innervating the wing margin bristles. Conclusions:We suggest SPL deficiency as a cause of a distinct form of Charcot-Marie-Tooth disease in humans, thus extending the currently recognized clinical and genetic spectrum of inherited peripheral neuropathies. Our data emphasize the importance of sphingolipid metabolism for neuronal function. Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of peripheral neuropathies affecting 1:2,500 individuals. 1 CMT is characterized by progressive length-dependent degeneration of peripheral motor and sensory neurons, resulting in distal muscles weakness and wasting, motor impairment, sensory loss, and skeletal deformities. The disease is classified into CMT1, with median motor nerve conduction velocities (NCVs) ,38 m/s and histologic evidence of demyelination and remyelination; CMT2, with normal or slightly reduced NCVs and axonal changes; and intermediate CMT, with NCVs ranging between 25 and 45 m/s and histopathologic signs of both demyelination and axonal degeneration. 2,3 CMT shows all modes of inheritance, with autosomal recessive forms (AR-CMT) accounting for ,10% of the European CMT population.4 This is likely underestimated due to the usually small sibship size, with many AR-CMT cases being considered sporadic. There are .24

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

“…(OMIM #617575) (19-21), but also with axonal peripheral neuropathy without renal or adrenal deficiencies (22).…”

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

“…Additional evidence is beginning to implicate sphingolipids in other forms of CMT. Deficiency of the gene responsible for clearing sphingolipids, sphingosine 1-phosphate (S1P) lyase, was recently discovered to be a novel cause of CMT, with a greatly increased sphingosine:sphinganine ratio in the disease state (58), yet a relatively much smaller increase in S1P levels. Such a drastic alteration of sphingosine:sphinganine ratio content without a similar increase in S1P from S1P lyase dysfunction is difficult to explain from simple, canonic, mechanistic models of sphingolipid metabolism and suggests that alterations to sphingolipid networks may produce dramatic and complex effects on sphingolipid content and metabolism in the cell.…”

Drosophila Imaginal Discs as a Playground for Genetic Analysis: Concepts, Techniques and Expectations for Biomedical Research

“…A successful example of the first approach, unbiased genetic screens, involved a mosaic screen of newly generated lethal mutations in the X chromosome that allowed the identification of 21 novel genes associated with human diseases for which no mutations were previously known [87]. The analysis of Drosophila genes with human counterparts contributing to human diseases has been mostly applied in the context of several neurodegenerative diseases, and some examples are the analysis of parkin and Pink1, genes related to Parkinson disease, and sphingosine-1-P-lyase for Charcôt-Marie-Tooth neuropathy [88]. In these cases, the Drosophila model allows a first approximation to study the functional relevance of the gene, including the consequences of its loss, its expression, the subcellular localization of the protein and its biochemical characteristics.…”