Affected and unaffected members of a family with an axonal form of peripheral neuropathy (classified as Charcot-Marie-Tooth type 2), with an autosomal recessive pattern of inheritance, were assessed by whole exome sequencing (WES). Based on the observation of compound heterozygous mutations in affected individuals, the WES analysis implicated the gene sphingosine 1-phosphate lyase 1 (SGPL1). There is a single orthologous gene in Drosophila, Dmel\Sply, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated. The human SGPL1 gene has also been implicated in nephrotic syndrome, type 14 (MIM:617575; FBhh0000616).
The human SGPL1 gene has not been introduced into flies.
Flies homozygous for a Sply loss-of-function insertional mutation exhibit compromised muscle development, decreased fecundity, and semi-lethality. In animals subjected to RNAi-effected knockdown of Sply expression using a pan-neuronal driver, phenotypes in the larval neuromuscular junctions have been assessed; reduced NMJ arborization and decreased the number of synaptic boutons are observed. Additional experiments indicate that neuronal depletion of Sply induces progressive axonal degeneration in Drosophila. A small number of genetic and physical interactions have been described for Dmel\Sply; see below and in the Sply gene report.
[updated Mar. 2019 by FlyBase; FBrf0222196]
Charcot-Marie-Tooth disease (CMT) constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. CMT is divided into several major types: Type 1 is characterized by demyelination and by a significantly slowed motor median nerve conduction velocity (NCV). Type 2 is characterized by axonal abnormalities and a normal or slightly reduced NCV. "Intermediate" types describe CMT families with nerve conduction velocities, in different affected individuals, that overlap the division between Type 1 and Type 2. Additional types are defined on the basis inheritance patterns. [from MIM:609260 and MIM:606482; 2015.12.15]
Symptoms typically include progressive distal muscle weakness and atrophy, often associated with mild to moderate sensory loss, depressed tendon reflexes, and high-arched feet. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK1358 2015.12.15]
The disease segregating in the characterized family is described as a type of Charcot-Marie-Tooth disease 2 (CMT2), with an atypical disease course. The associated phenotype is distinct from other CMT2 subtypes and is characterized by acute/subacute onset, unilateral motor deficit in one patient, and episodes of mononeuropathy with a tendency for improvement in both patients.
See general description of Charcot-Marie-Tooth disease, above.
Within the family characterized, consistent with autosomal recessive inheritance.
In a sural nerve biopsy, ~20% of nerve fibers showed active axonal disintegration.
Neurons depend on sphingolipids for axon guidance, neurotrophin signaling, and synaptic transmission.
Sphingosine-1-phosphate is a signaling sphingolipid that participates in various proliferative signal transduction pathways; its synthesis is catalyzed by sphingosine kinase and its degradation is catalyzed by sphingosine-1-phosphate lyase (SGPL1). [from MIM:603729; 2017.05.30]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human SGPL1 (1 Drosophila to 1 human); Dmel\Sply shares 50% identity and 69% similarity with the human gene.
