Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome

Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism

Colour Blind Discourses in Paid Domestic Work: Foreignness and the Delineation of Alternative Racial Markers

This paper explores how current shifts in racial discourse and demographics are reflected within the negotiation of paid domestic work. Various scholars have pointed out that racism in the United States has become increasingly covert and institutionalized, void of racial terminology and invisible to most whites. This shift has been institutionalized in the negotiation of domestic work, as alternative racial markers such as language and citizenship replace explicit racial terminology. Through an analysis of thirty interviews with white women who employ domestic workers this research examines contemporary negotiations of racial privilege and subordination in domestic work. Overall, white employers insisted that race did not matter when making hiring decisions; however other cultural markers such as language mattered greatly, at times even resulting in firing. In addition, complex and contradictory narratives about immigration were used to simultaneously both vilify immigrant workers and romanticize their work experiences