A Sphingosine-1-Phosphate Lyase Mutation Associated With Congenital Nephrotic Syndrome and Multiple Endocrinopathy

Abstract

Background: Loss of function mutations in SGPL1 are associated with Sphingosine-1-phosphate lyase insufficiency syndrome, comprising steroid resistant nephrotic syndrome, and primary adrenal insufficiency (PAI) in the majority of cases. SGPL1 encodes sphingosine-1-phosphate lyase (SGPL1) which is a major modulator of sphingolipid signaling. Case Presentation: A Pakistani male infant presented at 5 months of age with failure to thrive, nephrotic syndrome, primary adrenal insufficiency, hypothyroidism, and hypogonadism. Other systemic manifestations included persistent lymphopenia, ichthyosis, and motor developmental delay. Aged 9 months, he progressed rapidly into end stage oligo-anuric renal failure and subsequently died. Sanger sequencing of the entire coding region of SGPL1 revealed the novel association of a rare homozygous mutation (chr10:72619152, c.511A>G, p.N171D; MAF−1.701e-05) with the condition. Protein expression of the p.N171D mutant was markedly reduced compared to SGPL1 wild type when overexpressed in an SGPL1 knockout cell line, and associated with a severe clinical phenotype. Conclusions: The case further highlights the emerging phenotype of patients with loss-of-function SGPL1 mutations. Whilst nephrotic syndrome is a recognized feature of other disorders of sphingolipid metabolism, sphingosine-1-phosphate lyase insufficiency syndrome is unique amongst the sphingolipidoses in presenting with multiple endocrinopathies. Given the multi-systemic and progressive nature of this form of PAI/ nephrotic syndrome, a genetic diagnosis is crucial for optimal management and appropriate screening for comorbidities in these patients.

Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction

“…In 2017, Prasad et al [ 4 ], Lovric et al [ 5 ] and Janecke et al [ 6 ], described a series of patients with loss of function mutations in SGPL1 and a novel syndrome involving primary adrenal insufficiency and steroid resistant nephrotic syndrome. Since the initial publications several case reports have emerged, in total 35 genetically confirmed cases have been published involving 20 kindreds and 20 different mutations in SGPL1 , only one of which, R222Q, has been described in more than one kindred [ [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] ]. This disorder is often lethal, with 16 deaths reported among the 35 published cases (in addition to 4 intrauterine deaths).…”

The apoM/S1P Complex—A Mediator in Kidney Biology and Disease?

“…In humans, sphingosine-1-phosphate lyase (SGPL1) deficiency has been linked to nephrotic syndrome. SGLP1 mediates the degradation of S1P, meaning that deficiency results in accumulation of S1P and increased plasma levels, which further supports a causal role for S1P in kidney disease ( 111 – 113 ).…”

The role of lipid second messengers in aldosterone synthesis and secretion

“…Loss of function mutations in SGPL1 have been associated with primary adrenal insufficiency and steroid-resistant nephrotic syndrome in humans. (118)(119)(120) SGPL1 is expressed in normal human adrenals while adrenals from Sgpl -/mice shows compromised cortical zonation with less definition between the zG and zona fasciculata. Sgpl -/mouse adrenals also show lower expression of CYP11A1, while the characteristic patchy expression of aldosterone synthase (CYP11B2) in wild-type mice is replaced by a more continuous pattern of expression.…”