SGPL1 – Nephrotic syndrome 14

Sphingosine-1-phosphate lyase 1 (SGPL1) catalyzes the irreversible cleavage of sphingosine-1-phosphate, a key bioactive sphingolipid. Biallelic loss-of-function variants in SGPL1 cause a multisystemic sphingolipidosis, of which nephrotic syndrome 14 (Nephrotic syndrome 14) is a cardinal early manifestation. Affected individuals present in infancy with steroid-resistant nephrotic syndrome, often accompanied by primary adrenal insufficiency, ichthyosis, immunodeficiency, and neurological features.

SGPL1-related nephrotic syndrome is inherited in an autosomal recessive manner. Whole exome sequencing in seven unrelated families identified nine distinct recessive SGPL1 mutations segregating with disease in each pedigree (PMID:28165339). Multiple case reports have since expanded the allelic spectrum and confirmed recurrence of both missense and protein-truncating variants in diverse populations.

The variant spectrum includes missense substitutions (e.g., c.946G>A (p.Ala316Thr)), splice-site mutations, frameshifts, and nonsense alleles. Compound heterozygous and homozygous genotypes have been documented, with biallelic absence or reduction of SGPL1 activity correlating with early-onset renal failure and extrarenal features (PMID:28165339).

Functional studies in yeast complementation assays, Drosophila nephrocyte models, podocyte localization experiments, and patient-derived cell lines demonstrate that disease-associated variants abrogate SGPL1 activity, disrupt sphingolipid homeostasis, and impair cellular migration and morphology in nephron analogues. Rescue of function by wild-type SGPL1, but not mutant alleles, confirms pathogenicity in multiple systems.

Mechanistically, SGPL1 deficiency leads to sphingosine-1-phosphate accumulation, driving podocyte injury and apoptosis via dysregulated mitochondrial function and altered cell signaling. Concordant in vitro and in vivo data support a loss-of-function disease model and explain the syndromic renal and endocrine phenotype.

SGPL1 testing should be prioritized in infants with steroid-resistant nephrotic syndrome, especially when accompanied by adrenal insufficiency or ichthyosis. Early genetic diagnosis informs management, anticipatory screening for comorbidities, and family planning. Key take-home: SGPL1 biallelic variants cause a definitive autosomal recessive nephrotic syndrome 14 with consistent genotype–phenotype correlation and robust functional validation.

References

• The Journal of Clinical Investigation • 2017 • Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. PMID:28165339

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