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SPL Insufficiency Syndrome (SPLIS)
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SPL Insufficiency Syndrome (SPLIS)

Nephrotic syndrome is a clinical diagnosis given to patients who develop kidney disease due to failure of the kidney to properly filter the blood, resulting in loss of protein in the urine and reduced levels of some proteins found in the blood. Some patients with nephrotic syndrome respond to steroid hormone therapy, whereas others do not. Focal segmental glomerulosclerosis (FSGS) is the pathological entity responsible for most cases of steroid-resistant nephrotic syndrome (SRNS) and represents a significant cause of chronic kidney disease in children, adolescents and adults. Mutations in one of 27 genes known to cause FSGS can be detected in ~30% of individuals with SRNS manifesting before 25 years. In many patients, however, the genetic etiology remains unknown. Importantly, effective targeted therapies are currently lacking in FSGS.

Our laboratory in collaboration with the research groups of Friedhelm Hildebrandt and Corinne Antignac has established the role of inactivating mutations in the Sgpl1 gene encoding S1P lyase as a cause of FSGS. The patients also suffered from a variety of other defects including lymphopenia, other immunodeficiencies, adrenal insufficiency, acanthosis, central and peripheral nervous system abnormalities and endocrine defects. S1P lyase (SPL) is responsible for irreversible degradation of S1P, a bioactive signaling lipid found at highest levels in the blood. S1P serves as a ligand for a family of 5 ubiquitously expressed G protein-coupled receptors that are involved in the regulation of cell proliferation and migration, embryonic development, angiogenesis, lymphocyte and hematopoietic cell trafficking, and other physiological functions. When S1P lyase is absent or dysfunctional, aberrant S1P signaling and other metabolic consequences can result.

Using homozygosity mapping and whole exome sequencing in several families with FSGS, multiple different recessive mutations in Sgpl1 were identified. All identified mutations resulted in reduced or absent SPL expression and enzyme activity in patient fibroblasts and in HEK293 kidney cells expressing SPL with the disease-associated mutations. Furthermore, expression of wild type human SPL rescued growth of SPL-deficient yeast strains, whereas expression of disease-associated variant proteins did not. In Drosophila, mutants that lack SPL exhibited a phenotype reminiscent of nephrotic syndrome, and this phenotype was rescued by expression of wild type human SPL but not disease-associated variants. Our cumulative findings demonstrate that recessive Sgpl1 mutations cause a form of FSGS. Ongoing studies are aimed at establishing the mechanism by which SGPL1 deficiency syndrome causes nephrotic syndrome and other defects, determining whether aberrant S1P signaling underlies other forms of nephrotic syndrome, and identifying therapeutic strategies for SGPL1 deficient patients.

Lovric S, Goncalves S, Gee YH, Oskouian B, et al. SGPL1 mutations cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest 127(3):912-928, 2017.

See also:
SGPL1 mutations cause a novel SRNS syndrome


Revised: Tuesday, July 10, 2018 10:26 AM



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