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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.

BackgroundEarly diagnosis of girls with Turner syndrome (TS) is essential to provide timely intervention and support. The screening guidelines for TS suggest karyotype evaluation in patients presenting with short stature, webbed neck, lymphoedema, coarctation of aorta or ≥ two dysmorphic features. The aim of the study was to determine the age and clinical features at the time of presentation and to identify potential delays in diagnosis of TS.MethodsRetrospective data on age at diagnosis, reason for karyotype analysis and presenting clinical features was collected from the medical records of 67 girls with TS.ResultsThe mean age of diagnosis was 5.89 (±5.3) years ranging from pre-natal to 17.9 years (median 4.6 years). 10% were diagnosed antenatally, 16% in infancy, 54% in childhood (1–12 years) and 20% in adolescence (12–18 years). Lymphoedema (27.3%) and dysmorphic features (27.3%) were the main signs that triggered screening in infancy. Short stature was the commonest presenting feature in both childhood (52.8%) and adolescent (38.5%) years. At least 12% of girls fulfilled the criteria for earlier screening but were diagnosed only at a later age (mean age = 8.78 years). 13.4% of patients had classical 45XO karyotype and 52.3% of girls had a variant karyotype.ConclusionMajority of girls with TS were diagnosed only after the age of 5 years. Short stature triggered evaluation for most patients diagnosed in childhood and adolescence. Lack of dedicated community height-screening programme to identify children with short stature and lack of awareness could have led to potential delays in diagnosing TS. New strategies for earlier detection of TS are needed.

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The pituitary-derived somatolactotrophe GH3 cells secrete both growth hormone (GH) and prolactin (PRL). We have found that the hnRNP L and L-like (LL) paralogs differentially regulate alternative splicing of genes in these cells. Here, we show that hnRNP L is essential for PRL only, but LL is essential for both PRL and GH production. Transcriptome-wide RNA sequencing (RNA-Seq) analysis indicates that they differentially control groups of hormone or hormone-related genes involved in hormone production/regulation at total transcript and alternative exon levels. Interestingly, hnRNP L also specifically binds and prevents the aberrant usage of a nonconserved CA-rich intron piece of Prl pre-mRNA transcripts, and many others involved in endocrine functions, to prevent mostly cryptic last exons and mRNA truncation. Essential for the full hnRNP L effect on specific exons is a proline-rich region that emerged during evolution in vertebrate hnRNP L only but not LL. Together, our data demonstrate that the hnRNP L and its paralog, LL, differentially control hormone gene expression programs at multiple levels, and hnRNP L in particular is critical for protecting the transcriptome from aberrant usage of intronic sequences. The multilevel differential control by hnRNPs likely tailors the transcriptome to help refine and safeguard the different gene expression programs for different hormones.