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. 2017 Apr;38(4):365-372.
doi: 10.1002/humu.23192. Epub 2017 Mar 6.

Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications

Andreas R Janecke  1   2 , Ruijuan Xu  3   4 , Elisabeth Steichen-Gersdorf  1 , Siegfried Waldegger  1 , Andreas Entenmann  1 , Thomas Giner  1 , Iris Krainer  1 , Lukas A Huber  5 , Michael W Hess  6 , Yaacov Frishberg  7 , Hila Barash  8 , Shay Tzur  9   10 , Nira Schreyer-Shafir  11 , Rivka Sukenik-Halevy  11   12 , Tania Zehavi  13 , Annick Raas-Rothschild  8   12 , Cungui Mao  3   4 , Thomas Müller  1
Affiliations

Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications

Andreas R Janecke et al. Hum Mutat. 2017 Apr.

Abstract

We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome (CNS) diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing, two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1-encoding sphingosine-1-phosphate (S1P) lyase 1. SGPL1 catalyzes the irreversible degradation of endogenous and dietary S1P, the final step of sphingolipid catabolism, and of other phosphorylated long-chain bases. S1P is an intracellular and extracellular signaling molecule involved in angiogenesis, vascular maturation, and immunity. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry. Vascular alterations were present in a patient's renal biopsy, in line with changes seen in Sgpl1 knockout mice that are compatible with a developmental defect in vascular maturation. In conclusion, loss of SGPL1 function is associated with CNS, adrenal calcifications, and hypogonadism.

Keywords: adrenal calcification; congenital adrenal insufficiency; congenital nephrotic syndrome; developmental; hypergonadotropic hypogonadism; hypogonadism; sphingolipids; sphingosine-1-phosphate; vascular.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Pedigrees, clinical findings and SGPL1 mutations
A. Pedigree of family 1. Individuals II-1, II-2, III-1, III-2, and III-3 were available for mutation segregation analyses. B. Kidney biopsy of patient 2 at the age of 3 months (Masson’s stain) demonstrated focal segmental or global sclerosis, and hypertrophic thickened vessel walls and perivascular sclerosis of blood vessels. C. Pedigree of family 2. Individuals V-1, V-2, and VI-3 were available for mutation segregation analyses. D. Plain radiograph of patient 3 taken at 3 months of age shows bilateral adrenal calcifications (arrows). E. Sanger sequencing confirms the presence of a SGPL1 stop mutation in family 1 and a SGPL1 frameshift mutation in family 2 (F). The mutations are present in homozygous state in each patient and in heterozygous state in both parents of each patient (one carrier parent is shown in each case). Nucleotide numbering uses +1 as the A of the ATG translation initiation codon in the reference sequence, with the initiation codon as codon 1.
Figure 2
Figure 2
Outline of the metabolism of sphingolipids with emphasis on SGPL1.
Figure 3
Figure 3. The frameshift mutation in the SGPL1 gene alters blood and skin fibroblast sphingolipid levels
Blood samples were collected from healthy individuals (Control 1 and Control 2) and patient 3, and subjected to LC-MS/MS for the levels of sphingoid base phosphates, sphingoid bases, total ceramides, total dihydroceramides, total sphingomyelins, and total monohexosylceramides. Results for S1P (A), SPH (B), DHS1P (C), DHS (D), ceramide (E), dihydroceramide (F) are shown. The data represent mean values ± SD, n=3. *p<0.05. Skin fibroblasts from either healthy individuals (Control 1 and Control 2) and patient 3 were cultured to a 90% confluence in DMEM medium containing 20% FBS before being harvested for sphingolipid profiling by LC-MS/MS. The levels of sphingoid bases, sphingoid base phosphates, total ceramides, or total dihydroceramides were determined. In cultured skin fibroblasts, S1P (G), SPH (H), DHS1P (I), and DHS (K) were increased in the patient compared to healthy controls. For each sample, the data represent mean values from three measurements.
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