Abstract
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.
Highlights
Primary adrenal insufficiency (PAI) is most commonly congenital in children
Consanguineous kindred with 4 affected individuals with PAI, 2 of whom had steroid-resistant nephrotic syndrome, described as focal segmental glomerulosclerosis (FSGS) [9] (Figure 1, kindred 1)
The number of variants was reduced by the following strategy: (i) identifying variants that were common to both individuals; (ii) excluding variants that were heterozygous; (iii) removing variants, annotated in SNP databases, with a minor allele frequency of greater than 0.01; and (iv) evaluating nonsynonymous coding variants, splice variants, and indels only
Summary
Primary adrenal insufficiency (PAI) is most commonly congenital in children. Manifestations can include hyperpigmentation, failure to thrive, and a poor response to illness, with hypoglycemia and hypotension. Reduced life expectancy is described, and the condition can be fatal if undetected. It is genetically heterogeneous, with some gene defects causing syndromic. Our group has previously identified a number of genes in adrenal insufficiency syndromes [3,4,5,6,7,8]; within our patient cohort (n > 350), the genetic cause is currently unknown for 38% of cases, rendering their prognosis uncertain. Consanguineous kindred with 4 affected individuals with PAI, 2 of whom had steroid-resistant nephrotic syndrome, described as focal segmental glomerulosclerosis (FSGS) [9] (Figure 1, kindred 1). Mutations identified in a candidate gene were sought in the remainder of our cohort and in patients manifesting FSGS alone
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