Searchable abstracts of presentations at key conferences in endocrinology

ea0050s8.2 | Adrenal - in health and disease | SFEBES2017

ACTH signalling and resistance

Chan Li

The melanocortin-2-receptor (MC(2) receptor), also known as the ACTH receptor, is a critical component of the hypothalamic-pituitary-adrenal axis. The importance of MC(2) receptor in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC(2) receptor mutations cause ~25% of cases. The discovery of a MC(2) receptor accessory protein MRAP, mutations of which account...

ea0050s8.2 | Adrenal - in health and disease | SFEBES2017

ACTH signalling and resistance

Chan Li

The melanocortin-2-receptor (MC(2) receptor), also known as the ACTH receptor, is a critical component of the hypothalamic-pituitary-adrenal axis. The importance of MC(2) receptor in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC(2) receptor mutations cause ~25% of cases. The discovery of a MC(2) receptor accessory protein MRAP, mutations of which account...

ea0065cc2 | FEATURED CLINICAL CASE POSTERS | SFEBES2019

Splice-site mutations in the melanocortin-2 receptor accessory protein that lead to early-onset familial glucocorticoid deficiency type 2

Qamar Younus , Maharaj Avinaash , Chan Li , Deeb Asma , Metherell Louise

Background: Familial glucocorticoid deficiency (FGD) is characterised by isolated glucocorticoid deficiency, with preserved mineralocorticoid production. FGD type 2 is caused by mutations in MRAP encoding the melanocortin-2 receptor accessory protein. MRAP has a single transmembrane domain essential to its function in trafficking the MC2R/ACTH receptor. 15 mutations in MRAP have been described, five of which are within the canonical donor splice-site of intro...

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...

ea0028p311 | Steroids | SFEBES2012

Adrenal expression of the melanocortin-2-receptor and its accessory proteins during sepsis.

Gorrigan Rebecca , Elias Lucila , Clark Adrian , Chan Li

Background: The melanocortin 2 receptor (MC2R)/melanocortin 2 receptor accessory protein (MRAP) are critical components of the hypothalamo-pituitary-adrenal axis (HPA). MRAP2, homologue of MRAP, can also regulate the MC2R in vitro, however, the physiological significance of this is unclear. We studied the expression of the MRAPs and MC2R in a well-defined rat model of endotoxin induced septic shock. These animals have been shown to have higher ACTH and corticosterone le...

ea0025p306 | Steroids | SFEBES2011

Why does MRAP2 fail to save familial glucocorticoid deficiency type 2 patients?

Gorrigan Rebecca , Guasti Leonardo , Clark Adrian , Chan Li

Background and aims: The melanocortin-2-receptor accessory protein (MRAP) is essential for melanocortin-2-receptor (MC2R) function through receptor trafficking and signalling, enabling adrenal glucocorticoid synthesis in response to ACTH stimulation. Disabling mutations of MRAP result in life-threatening glucocorticoid deficiency, known as familial glucocorticoid deficiency type 2. MRAP has a single paralogue in the human genome, MRAP2. In vitro MRAP2 has a similar acti...

ea0013s66 | Dealing with MEN | SFEBES2007

Dealing with MEN: A paediatric perspective

Martin Lee , Chan Li , Savage MO , Johnston LB

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant condition that is rare in childhood. MEN2 is sub-classified into three categories that all include familial medullary thyroid carcinoma (MTC). Familial MTC has no other associated tumours. MEN2A is characterised by MTC, phaeochromocytoma and parathyroid tumours and MEN2B consists of MTC, phaeochromocytoma, ganglioneuromatosis and usually a Marfanoid habitus. The identification of RET as the causative gene has ...

ea0094oc5.2 | Adrenal and Cardiovascular | SFEBES2023

Gain-of-function mutation F278C in MC2R results in reduced beta-1-arrestin recruitment and increased cAMP implicating impairment of S280 phosphorylation

Popat Dillon , Xu Ruoyan , McCormick Peter , Chan Li

The adrenocorticotrophin hormone (ACTH) receptor, also known as the melanocortin-2-receptor (MC2R), is a key mediator of cortisol synthesis in the adrenal gland. Over 40 loss-of-function MC2R mutations have been described to give rise to familial glucocorticoid deficiency type-1 (FGD1). In contrast, to date only one naturally occurring gain-of-function mutation, F278C, has been identified in a patient with ACTH-independent CushingÂ’s syndrome. Previous work has demonstrate...

ea0095oc2.1 | Oral Communications 2 | BSPED2023

A novel maternally inherited GNAS variant in a family with hyperphagia and obesity

Purushothaman Preetha , Popat Dillon , Ramakrishnan Anand , Chan Li , Gevers Evelien

Introduction: Heterozygous inactivating mutations in the maternal allele of the GNAS gene typically result in pseudohypoparathyroidism (PHP). GNAS variants were recently described in 1% of patients, not known to have PHP, in the UK Genetics of Obesity cohort, resulting in reduced MC4R signalling and variable effects on PTH-R and GHRH-R signalling.Methods: NGS (Cambridge Obesity Gene Panel) and in vitro functiona...

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...