Akademik Veri Yönetim Sistemi
JOURNAL OF CLINICAL INVESTIGATION, cilt.127, sa.3, ss.942-953, 2017 (SCI-Expanded)
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-offunction 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.