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

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.

A new genetic isolate with a unique phenotype of syndromic oculocutaneous albinism: clinical, molecular, and cellular characteristics.

An extended, highly consanguineous Israeli Bedouin family with at least 20 individuals exhibiting a unique phenotype of oculocutaneous albinism (OCA) was identified. All known OCA genes were excluded in this family. Electron microscopic analysis of platelets revealed absence of dense bodies, suggesting a diagnosis of Hermansky-Pudlak syndrome (HPS). HPS is a rare autosomal recessive disorder of lysosome-related organelle biogenesis, clinically characterized by OCA and platelet dysfunction, sometimes accompanied by other systemic pathologies. All human HPS genes (HPS1-8) and five genes corresponding to murine HPS models were evaluated. Haplotype analysis and homozygosity mapping of the HPS loci revealed linkage to chromosome 10 in the studied family. Subsequently, a novel insertion mutation, c.1066-1067insG was identified in HPS6. Most frameshift mutations generating premature termination codon cause mRNA nonsense mediated decay (NMD), while intronless genes like HPS6 are usually not monitored by NMD. Expression analysis revealed no mRNA decay in patient's fibroblasts, hence truncated protein is most probably produced. Confocal microscopy revealed abnormal distribution of LAMP-3 (lysosomal associated membrane protein-3) in fibroblasts from the patients, indicating abnormal trafficking of lysosomal lineage organelles. So far, a single HPS-6 patient phenotypically similar to HPS-3 and HPS-5 has been identified. The HPS-6 phenotype in the studied family is unique since it resembles OCA and not HPS. Therefore, our finding broadens the phenotypic definition of HPS. Two major genetic isolates of HPS-1 and HPS-3 patients were previously diagnosed in Puerto Rico. The extended Bedouin family is the largest isolate of non-Puerto Rican HPS patients.