Familial glucocorticoid deficiency (FGD), or hereditary unresponsiveness to adrenocorticotropin (ACTH; OMIM 202200), is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood. Mutations of the ACTH receptor (melanocortin 2 receptor, MC2R) account for approximately 25% of cases of FGD. FGD without mutations of MC2R is called FGD type 2. Using SNP array genotyping, we mapped a locus involved in FGD type 2 to chromosome 21q22.1. We identified mutations in a gene encoding a 19-kDa single-transmembrane domain protein, now known as melanocortin 2 receptor accessory protein (MRAP). We show that MRAP interacts with MC2R and may have a role in the trafficking of MC2R from the endoplasmic reticulum to the cell surface.

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Familial isolated pituitary adenoma (FIPA) is an autosomal dominant condition with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene have been reported in 15–40% of FIPA patients. Limited data are available on the functional consequences of the mutations or regarding the regulation of the AIP gene. We describe a large cohort of FIPA families and characterize missense and silent mutations using minigene constructs, luciferase and β-galactosidase assays, as well as in silico predictions. Patients with AIP mutations had a lower mean age at diagnosis (23.6±11.2 years) than AIP mutation-negative patients (40.4±14.5 years). A promoter mutation showed reduced in vitro activity corresponding to lower mRNA expression in patient samples. Stimulation of the protein kinase A-pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing resulting in truncated protein or reduced AIP expression. A two-hybrid assay of protein–protein interaction of all missense variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In summary, exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in our FIPA cohort. Functional characterization of AIP changes is important to identify the functional impact of gene sequence variants. Hum Mutat 31:1–11, 2010. © 2010 Wiley-Liss, Inc.

In Saccharomyces cerevisiae, two components of the RNA polymerase III (Pol III) general transcription factor TFIIIB are the TATA-binding protein (TBP) and the B-related factor (BRF), so called because its amino-terminal half is homologous to the Pol II transcription factor IIB (TFIIB). We have cloned BRF genes from the yeasts Kluyveromyces lactis and Candida albicans. Despite the large evolutionary distance between these species and S. cerevisiae, the BRF proteins are conserved highly. Although the homology is most pronounced in the amino-terminal half, conserved regions also exist in the carboxy-terminal half that is unique to BRF. By assaying for interactions between BRF and other Pol III transcription factors, we show that it is able to bind to the 135-kD subunit of TFIIIC and also to TBP. Surprisingly, in addition to binding the TFIIB-homologous amino-terminal portion of BRF, TBP also interacts strongly with the carboxy-terminal half. Deleting two conserved regions in the BRF carboxy-terminal region abrogates this interaction. Furthermore, TBP mutations that selectively inhibit Pol III transcription in vivo impair interactions between TBP and the BRF carboxy-terminal domain. Finally, we demonstrate that BRF but not TFIIB binds the Pol III subunit C34 and we define a region of C34 necessary for this interaction. These observations provide insights into the roles performed by BRF in Pol III transcription complex assembly.

Context The effects of COVID-19 on the thyroid axis remain uncertain. Recent evidence has been conflicting, with both thyrotoxicosis and suppression of thyroid function reported. Objective We aimed to detail the acute effects of COVID-19 on thyroid function and determine if these effects persisted on recovery from COVID-19. Design A cohort observational study was conducted. Participants and Setting Adult patients admitted to Imperial College Healthcare National Health Service Trust, London, UK, with suspected COVID-19 between March 9 to April 22, 2020, were included, excluding those with preexisting thyroid disease and those missing either free thyroxine (FT4) or thyrotropin (TSH) measurements. Of 456 patients, 334 had COVID-19 and 122 did not. Main Outcome Measures TSH and FT4 measurements were recorded at admission, and where available, in 2019 and at COVID-19 follow-up. Results Most patients (86.6%) presenting with COVID-19 were euthyroid, with none presenting with overt thyrotoxicosis. Patients with COVID-19 had a lower admission TSH and FT4 compared to those without COVID-19. In the COVID-19 patients with matching baseline thyroid function tests from 2019 (n = 185 for TSH and 104 for FT4), TSH and FT4 both were reduced at admission compared to baseline. In a complete case analysis of COVID-19 patients with TSH measurements at follow-up, admission, and baseline (n = 55), TSH was seen to recover to baseline at follow-up. Conclusions Most patients with COVID-19 present with euthyroidism. We observed mild reductions in TSH and FT4 in keeping with a nonthyroidal illness syndrome. Furthermore, in survivors of COVID-19, thyroid function tests at follow-up returned to baseline.

The use of splice‐switching antisense therapy is highly promising, with a wealth of pre‐clinical data and numerous clinical trials ongoing. Nevertheless, its potential to treat a variety of disorders has yet to be realized. The main obstacle impeding the clinical translation of this approach is the relatively poor delivery of antisense oligonucleotides to target tissues after systemic delivery. We are a group of researchers closely involved in the development of these therapies and would like to communicate our discussions concerning the validity of standard methodologies currently used in their pre‐clinical development, the gaps in current knowledge and the pertinent challenges facing the field. We therefore make recommendations in order to focus future research efforts and facilitate a wider application of therapeutic antisense oligonucleotides.

SDH-B mutation carriers develop disease early and predominantly in extra-adrenal locations. Disease penetrance is incomplete. Metastatic disease is prominent but levels are less than previously reported. Clinical manifestations may include papillary renal cell carcinoma and macrovascular disease.

Prader-Willi syndrome (PWS) is characterized by life-threatening childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone. Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 microg/hr) or saline for 300 min, and had blood samples taken every 30 min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60 min free food access period from +120 min. Despite somatostatin lowering fasting plasma ghrelin by 60 +/- 2% (P = 0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 +/- 9% of food intake during saline infusion, P = 0.6). Somatostatin also lowered plasma PYY levels by 45 +/- 16% (P = 0.04), and produced post-prandial hyperglycemia (P = 0.04). We conclude that either hyperghrelinemia may not contribute to hyperphagia in PWS adults, or perhaps concomitant reductions in anorexigenic gastrointestinal hormones by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for obesity in PWS. Larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity.