Searchable abstracts of presentations at key conferences in endocrinology

ea0044p27 | Adrenal and Steroids | SFEBES2016

Structural analysis of nicotinamide nucleotide transhydrogenase (NNT) genetic variants causing adrenal disorders

Metherell Lou , Guerra-Assuncao Jose Afonso , Sternberg Michael , David Alessia

Nicotinamide nucleotide transhydrogenase (NNT) is an integral protein of the inner mitochondrial membrane and plays a major role in maintaining the redox balance by catalysing the trans-hydrogenation between NADH and NADP+ and proton translocation across the mitochondrial membrane.Genetic variants in NNT have recently been reported in patients with familial glucocorticoid deficiency (FGD), combined mineralocorticoid and glucocorticoid deficiency...

ea0039oc5.2 | Oral Communications 5 | BSPED2015

Genetic characterisation of children with short stature and GH or IGF1 insensitivity by single gene and whole exome sequencing

Shapiro Lucy , Savage Martin , Metherell Lou , Storr Helen

Background: GH insensitivity (GHI) encompasses growth failure, low serum IGF1 and normal/elevated serum GH. IGF1 insensitivity results in pre- and postnatal growth failure with normal/relatively high IGF1 levels.Objective: To undertake candidate gene (CGS) and whole exome (WES) sequencing to obtain a genetic diagnosis in children with short stature and GHI or IGF1 insensitivity.Methods: As a referral centre for GHI genetics, since ...

ea0038oc3.1 | Steroids and adrenal | SFEBES2015

Molecular diagnosis of patients with adrenal insufficiency using a targeted custom Haloplex next-generation sequencing panel

Buonocore Federica , Chan Li , Achermann John , Metherell Lou

Background: Gaining a correct genetic diagnosis for patients with adrenal insufficiency is important not only to enable genetic counselling within their families, but also for correct treatment and long term management. Adrenal insufficiency is genetically heterogeneous and the long-term sequelae for many of the gene defects, including the progression of the disease and involvement of other tissues, is unknown. Next-generation sequencing (NGS) technologies allow parallel seque...

ea0027s16 | Symposium 1–Update on Adrenal Disorders | BSPED2011

Familial glucocorticoid deficiency: an update

Clark Adrian J L , Hughes Claire , Meimaridou Eirini , Metherell Lou

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by resistance to the action of ACTH leading to glucocorticoid deficiency with preserved mineralocorticoid and gonadal function. In 1993 we identified mutations in the ACTH receptor (melanocortin 2 receptor; MC2R), although these only explained around 25% of cases. More recently a traditional homozygosity mapping approach identified mutations in a novel gene which we named melan...

ea0014oc9.1 | Signal transduction | ECE2007

Investigation of the role of MRAP in the functional expression of the melanocortin 2 receptor

Cooray Sadani , Metherell Lou , Cheetham Mike , Clark Adrian

Mutations in the ACTH receptor (Melanocortin 2 receptor/MC2R) are associated with Familial Glucocorticoid Deficiency/FGD. FGD is an autosomal recessive disorder that results from ACTH insensitivity at the adrenal cortex. However, only about 25% of FGD are caused by mutations in the MC2R suggesting the genetically heterogeneous nature of the disease. The transfection-mediated functional expression of the MC2R can only be achieved in cell lines of adrenal origin implying that th...

ea0077p11 | Adrenal and Cardiovascular | SFEBES2021

SGPL1 regulates expression of electron transport chain components to modulate cellular metabolism in the adrenal gland

Williams Jack , Smith Chris , Maharaj Avinaash , Kwong Ruth , Hall Charlotte , Metherell Lou , Prasad Rathi

Introduction: Sphingosine-1-phosphate lyase (SGPL1) catalyses the final step in sphingolipid metabolism, irreversibly degrading the lipid signalling molecule sphingosine-1-phosphate (S1P). The relative abundance of S1P compared to its precursors sphingosine and ceramide finely tunes signal transduction for a wide range of cellular pathways including proliferation, apoptosis, migration and calcium handling. Loss-of-function mutations in SGPL1 cause a spectrum of disorders, incl...

ea0077p134 | Adrenal and Cardiovascular | SFEBES2021

In vitro splicing assay proves the pathogenicity of intronic variants in MRAP

Smith Chris , Maharaj Avinaash , Qamar Younus , Read Jordan , Williams Jack , Marimuthu Vidhya , Chan Li , Metherell Lou

Familial glucocorticoid deficiency (FGD) is characterised by isolated glucocorticoid deficiency with retention of normal mineralocorticoid production. FGD causing mutations in the MC2R accessory protein, MRAP, often occur at the canonical donor splice-site of intron 3, presumed to result in skipping of the first coding exon with unknown consequences at the protein level. DNA from three patients (0 - 6 months) with high ACTH and/or low cortisol levels underwent whole e...

ea0051p010 | Adrenal | BSPED2017

An unusual presentation of congenital lipoid adrenal hyperplasia and novel STAR mutation in two siblings

Andrews Edward , Taylor Carl , Metherell Lou , Buonocore Frederica , Achermann John , Maharaj Avinaash , Davies Justin H

Introduction: Congenital lipoid adrenal hyperplasia (CLAH) is rare and caused by mutations in the steroidogenic acute regulatory (STAR) gene, which is involved in a key step in the synthesis of pregnenolone from cholesterol. Cases typically present in the first days of life with severe adrenal crisis, salt wasting and severely disrupted androgen secretion which may result in sex reversal in 46, XY individuals.Case report: We present a 21-month-o...

ea0085oc5.8 | Oral Communications 5 | BSPED2022

SGPL1 deficiency impairs Leydig cell steroidogenesis and should be considered in 46XY individuals with DSD and adrenal insufficiency

Ming Wai Kwong Ruth , Williams Jack , Maharaj Avinaash V , Metherell Lou , Prasad Rathi

Sphingosine-1-phosphate lyase 1 insufficiency syndrome (SPLIS) is a multisystemic syndrome in which primary adrenal insufficiency (PAI) and steroid resistant nephrotic syndrome predominate, secondary to loss-of-function mutations in SGPL1 (sphingosine-1-phosphate lyase). SGPL1 carries out the irreversible breakdown of sphingosine-1-phosphate, a bioactive sphingolipid intermediate, with implicated roles in various cellular processes. Wider endocrinopathy including gonadal insuf...

ea0038oc1.3 | Early Career Oral Communications | SFEBES2015

RNA-sequencing of mouse adrenals reveals the pathways perturbed by loss of nicotinamide nucleotide transhydrogenase

Meimaridou Eirini , Goldsworthy Michelle , Chortis Vasileios , Foster Paul , Arlt Wiebke , Cox Roger , Metherell Lou

Nicotinamide nucleotide transhydrogenase (NNT) is a highly conserved inner mitochondrial membrane protein, which supplies high concentrations of NADPH for detoxification of reactive oxygen species (ROS) by glutathione and thioredoxin pathways. In humans, loss-of-function mutations in NNT cause familial glucocorticoid deficiency, a potentially fatal, adrenal specific disorder characterized by increased levels of ACTH and low levels of cortisol. Nnt−...