Alternative titles; symbols
HGNC Approved Gene Symbol: SGPL1
Cytogenetic location: 10q22.1 Genomic coordinates (GRCh38): 10:70,815,948-70,881,184 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.1 | RENI syndrome | 617575 | Autosomal recessive | 3 |
The SGPL1 gene encodes sphingosine-1-phosphate lyase-1, an endoplasmic reticulum (ER) enzyme that is involved in sphingolipid catabolism. It catalyzes the final step of the sphingolipid breakdown pathway, initiating irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P) (summary by Prasad et al., 2017).
Sphingosine-1-phosphate (SPP) participates in the proliferative signal transduction pathways of mammalian cells. SPP synthesis is catalyzed by sphingosine kinase (603730), and SPP degradation is catalyzed by SPP lyase (SPL). The first SPL gene cloned, BST1 ('bestowed of sphingosine tolerance'), was isolated from budding yeast (Saba et al., 1997). A yeast mutant strain containing a deletion of the entire BST1 coding region is sensitive to the growth-inhibitory effects of D-erythro-sphingosine, due to its inability to degrade SPP. Zhou and Saba (1998) identified a mouse cDNA encoding a protein, which they named Spl, that has 59% sequence similarity to the BST1 gene product. They showed that this cDNA can functionally complement the yeast BST1 deletion, restoring a sphingosine-resistant phenotype. Northern blot analysis detected Spl expression in several mouse tissues, with the highest level found in the liver.
Prasad et al. (2017) found ubiquitous expression of SGPL1 in human tissues, with moderate levels of expression in the adrenal cortex and kidneys and high levels of expression in the testes and thyroid.
In mouse kidney, Lovric et al. (2017) found expression of Sgpl1 in podocytes, as well as in other renal glomerular cell types, including mesangial and endothelial cells. Sgpl1 colocalized with ER markers.
Using interspecific backcross mapping, Zhou and Saba (1998) localized the mouse Spl gene to chromosome 10, between the Eif4ebp2 (602224) and Egr2 (129010) genes. By homology of synteny, they mapped the human homolog of Spl, SGPL1, to 10q21.
Lymphocyte egress from the thymus and from peripheral lymphoid organs depends on sphingosine 1-phosphate (S1P) receptor-1 (601974) and is thought to occur in response to circulatory S1P. To further define gene egress requirements, Schwab et al. (2005) addressed why treatment with the food colorant 2-acetyl-4-tetrahydroxybutylimidazole (THI) induces lymphopenia. Schwab et al. (2005) found that S1P abundance in lymphoid tissues of mice is normally low but increases more than 100-fold after TH1 treatment and that this treatment inhibits the S1P-degrading enzyme sphingosine 1-phosphate lyase (SGPL1). Schwab et al. (2005) concluded that lymphocyte egress is mediated by S1P gradients that are established by S1P lyase activity and that the lyase may represent a novel immunosuppressant drug target.
In 8 patients from 5 unrelated families with RENI syndrome (RENI; 617575), Prasad et al. (2017) identified homozygous loss-of-function mutations in the SGPL1 gene (see, e.g., 603729.0001-603729.0004). All but 1 of the families were consanguineous. The mutations were found by whole-exome or Sanger sequencing and segregated with the disorder in the families. Cellular expression assays of 2 of the mutations (R222Q, 603729.0001 and F545del, 603729.0002) showed that they resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function.
In patients from 7 unrelated, mostly consanguineous families of various ethnic origins with RENI syndrome, Lovric et al. (2017) identified homozygous or compound heterozygous mutations in the SGPL1 gene (see, e.g., 603729.0001; 603729.0004-603729.0006). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing; subsequent mutations were found by whole-exome sequencing or Sanger sequencing. All mutations segregated with the disorder in the families. The mutation spectrum included frameshift, splice site, and missense mutations, and all were associated with reduced or absent SGPL1 protein and/or enzyme activity as measured in patient fibroblasts or transfected cells. Detailed functional studies of 2 of the missense mutations (R222Q and S346I, 603729.0006) showed a loss-of-function effect, with reduced protein levels, enzyme activity, impaired degradation of long-chain sphingoid bases, and altered subcellular localization. Disease-associated variants were unable to rescue growth defects in yeast or abnormalities in Drosophila deficient in Sgpl1. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, and patient fibroblasts showed reduced cell migration compared to controls.
In 2 unrelated male patients, both born of consanguineous parents, with RENI syndrome, Janecke et al. (2017) identified homozygous truncating mutations in the SGPL1 gene (603729.0007 and 603729.0008). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in blood and fibroblasts from one of the patients.
Settas et al. (2019) screened 21 patients with clinical features of primary adrenal insufficiency for variants in the SGPL1 gene and identified 2 patients with homozygosity and 2 with heterozygosity. The 2 patients with homozygosity were a 5.5-year-old proband, born of consanguineous parents, with RENI syndrome and his 15-year-old first cousin with the previously identified R222Q mutation (603729.0001). The 2 patients with heterozygosity had a missense variant (c.61G-T; V21L) that had an allele frequency of 0.09 in ExAC; the authors posited that this variant was unrelated to their adrenal insufficiency.
In a 15-year-old girl, born to consanguineous Turkish parents, with RENI syndrome, Maharaj et al. (2022) identified a homozygous missense mutation in the SGPL1 gene (c.1049A-G, chr10:72631733A-G, D350G). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Examination of SGPL1 protein levels in the patient by immunoblotting showed decreased expression of the D350G variant. CRISPR-engineered human adrenocortical cells with SGPL1 knockout showed minimal cortisol output.
In a set of Chinese identical twin girls with RENI syndrome, Yang et al. (2023) identified compound heterozygous intronic mutations in the SGPL1 gene (603729.0003 and 603729.0009). The mutations were found by exome sequencing and segregated with the disorder in the family. Yang et al. (2023) conducted a review of 31 patients in the literature with SGPL1 variants causing nephrotic syndrome, including their 2 patients. Twenty-five patients (80.6%) had homozygous mutations (15 missense, 8 frameshift, and 2 truncation) and 6 patients (19.4%) had compound heterozygous mutations.
Associations Pending Confirmation
Atkinson et al. (2017) described 2 Serbian sibs with acute or subacute onset of axonal peripheral neuropathy and episodes of recurrent mononeuropathy, which the authors called autosomal recessive Charcot-Marie-Tooth disease, who were compound heterozygous for mutations in the SGPL1 gene: c.551T-C, resulting in an ile184-to-thr (I184T) substitution, and c.1082C-G in exon 12 (of 15), resulting in a ser361-to-ter (S361X) substitution. The mutations cosegregated with the phenotype in the family. Plasma levels of sphingosine 1-phosophate and the sphingosine/sphinganine ratio were elevated in the patients, consistent with decreased sphingosine-1-phosphate lyase activity. The S361X variant appeared to result in nonsense-mediated decay based on the absence of the c.1082C-G allele on Sanger sequencing of SGPL1 cDNA from lymphoblasts. SGPL1 protein levels were nearly undetectable based on immunoblotting.
Prasad et al. (2017) found that adrenal cortical zonation was compromised in Sgpl1-null mice. Steroidogenesis also appeared to be disrupted. Kidneys from mutant mice showed mesangial hypercellularity and glomerular fibrosis, which recapitulated the main characteristics of NPHS14.
Lovric et al. (2017) found that the kidneys of Sgpl1-null mice showed complete foot process effacement and absence of slit diaphragms. Mutant mice also showed hypoalbuminemia and increased urinary albumin/creatinine ratio. Cultured podocytes from Sgpl1-null mice did not show evidence of increased apoptosis or abnormalities in cell migration. Knockdown of Sgpl1 in rat mesangial cells did not affect apoptosis or proliferation, but did have reduced migration. Certain S1PR antagonists partially rescued the migration defect. Studies of Drosophila with deficiency of the Sply ortholog of Sgpl1 showed a reduction of nephrocyte foot process density and reduced albumin uptake compared to controls. Mutant flies also showed evidence of altered lipid metabolism due to disruption of the sphingolipid catabolic pathway.
In 3 members of a highly consanguineous Pakistani family with RENI syndrome (RENI; 617575), originally reported by Ram et al. (2012), Prasad et al. (2017) identified a homozygous c.665G-A transition (chr10:72,628,151G-A) in the SGPL1 gene, resulting in an arg222-to-gln (R222Q) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in heterozygous state in 2 of 120,744 alleles in the ExAC database (frequency of 1.7 x 10(-5)). No homozygotes were found in the dbSNP, Exome Variant Server, or ExAC databases. Subsequently, the same mutation was found in a similarly affected individual, born of consanguineous Saudi parents, but haplotype analysis excluded a founder effect. Cellular expression assays showed that the mutation resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function.
Lovric et al. (2017) identified homozygosity for the R222Q mutation in the SGPL1 gene in 3 members of a consanguineous Pakistani family (A280) with RENI syndrome. The mutation was found by a combination of homozygosity mapping and whole-exome sequencing. Cellular expression studies showed that the mutation resulted in decreased protein levels and strongly decreased enzyme activity compared to wildtype, as well as formation of abnormal cytoplasmic SGPL1 aggregates. The mutant protein also failed to rescue growth defects in DPL1-deficient yeast, consistent with a loss of function. One of the patients had unusually late onset of renal disease at age 19 years.
In a 5.5-year-old boy, born to consanguineous Saudi Arabian parents, with RENI syndrome, and in his 15-year-old first cousin, Settas et al. (2019) identified homozygosity for a G-A transition (c.665G-A) in the SGPL1 gene, resulting in an arg222-to-gln (R222Q) substitution. The 15-year-old first cousin had amblyopia of the right eye, right-sided hearing loss, and right arm paralysis and developed kidney failure requiring hemodialysis; no further information on his phenotype was available.
In a female Turkish patient with RENI syndrome (RENI; 617575), Prasad et al. (2017) identified a homozygous in-frame 3-bp deletion (c.1633_1635delTTC) in the SGPL1 gene, resulting in the deletion of highly conserved residue Phe545. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not present in public databases. Cellular expression assays showed that the mutation resulted in decreased stability of the protein and almost complete absence of enzyme activity, consistent with a loss of function.
In 2 sibs, born of consanguineous Peruvian parents, with RENI syndrome (RENI; 617575), Prasad et al. (2017) identified a homozygous G-to-A transition (c.261+1G-A) in the SGPL1 gene, resulting in a splice site defect and predicting premature termination (Ser65ArgfsTer6). The mutant transcript was likely degraded by nonsense-mediated mRNA decay, resulting in a loss of function. The mutation segregated with the disorder in the family and was not found in any databases.
In a set of Chinese identical twin girls with RENI syndrome, Yang et al. (2023) identified compound heterozygous splicing mutations in the SGPL1 gene: c.261+1G-A (c.261+1G-A, NM_003901.4) in intron 4 and c.1298+6T-C (603729.0009) in intron 12. The mutations were found by exome sequencing, and each parent carried one of the mutations. The girls had steroid-resistant nephrotic syndrome with no extrarenal manifestations.
In a patient, born of consanguineous Spanish parents, with RENI syndrome (RENI; 617575), Prasad et al. (2017) identified a homozygous 1-bp duplication (c.7dupA) in the SGPL1 gene, resulting in a frameshift and premature termination (Ser3LysfsTer11). The mutation was not found in the ExAC database. The mutant transcript was likely degraded by nonsense-mediated mRNA decay, resulting in a loss of function.
In 3 affected members of a consanguineous Spanish Roma family (A5444) with RENI syndrome, Lovric et al. (2017) identified a homozygous c.7dupA mutation in exon 2 of the SGPL1 gene. The mutation was found by whole-exome sequencing and segregated with the disorder in the family.
In 4 members of a consanguineous Turkish family (EB) with RENI syndrome (RENI; 617575), Lovric et al. (2017) identified a homozygous c.664C-T transition in exon 8 of the SGPL1 gene, resulting in an arg222-to-trp (R222W) substitution at a highly conserved residue in the PLP-dependent transferase domain. The mutation was not found in the ExAC database. Functional studies of the variant were not performed, but a different mutation in the same codon was found in another family with NPHS14 (R222Q; 603729.0001). Patients in the EB family had a severe form of the disorder, with congenital nephrotic syndrome resulting in fetal demise or death in the first months of life.
In affected members of a large consanguineous Moroccan kindred (B46/B56) with RENI syndrome (RENI; 617575), Lovric et al. (2017) identified a homozygous c.1037G-T transversion in exon 11 of the SGPL1 gene, resulting in a ser346-to-ile (S346I) substitution at a highly conserved residue in the PLP-dependent transferase domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family and was not found in the ExAC database. Cellular expression studies showed that the mutation resulted in decreased protein levels and enzyme activity compared to wildtype, as well as formation of abnormal cytoplasmic SGPL1 aggregates. The mutant protein also failed to rescue growth defects in DPL1-deficient yeast, consistent with a loss of function.
In a male patient from a large consanguineous family of Arab descent with RENI syndrome (RENI; 617575), Janecke et al. (2017) identified a homozygous c.1513C-T transition (c.1513C-T, NM_003901.3) in the SGPL1 gene, resulting in an arg505-to-ter (R505X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, Exome Sequencing Project, or ExAC databases. The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. A similarly affected patient from the same family died at age 7 weeks; material from that patient was not available for study. The family had previously been reported by Schreyer-Shafir et al. (2014).
In a male patient, born of consanguineous parents, with RENI syndrome (RENI; 617575), Janecke et al. (2017) identified a homozygous 1-bp deletion (c.934delC, NM_003901.3) in the SGPL1 gene, resulting in a frameshift and premature termination (Leu312PhefsTer30). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, Exome Sequencing Project, or ExAC databases. The mutation was predicted to result in nonsense-mediated mRNA decay and a loss of function. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patient's blood and fibroblasts.
For discussion of the c.1298+6C-T mutation (c.1298+6C-T, NM_003901.4) in the SGPL1 gene that was found in compound heterozygous state in Chinese identical twin girls with RENI syndrome (RENI; 617575) by Yang et al. (2023), see 603729.0003.
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