Searchable abstracts of presentations at key conferences in endocrinology

ea0011s67 | Disorders of melanocortin receptor functions | ECE2006

Identification of the genes causing ACTH insensitivity

Clark AJL , Metherell LA

ACTH insensitivity or Familial Glucocorticoid Deficiency (FGD) is an autosomal recessive disorder that presents in early childhood usually with hypoglycaemia and seizures, infection or malaise and skin pigmentation. Plasma cortisol is low or undetectable and ACTH markedly elevated. Renin and aldosterone are not markedly disturbed. FGD results from mutations of the ACTH receptor in about 25% of cases. We have sought further genetic causes of this disorder using a homozygosity m...

ea0019p208 | Growth and development | SFEBES2009

Antisense oligonucleotides to correct the aberrant growth hormone receptor mRNA splicing caused by the pseudoexon 6Ψ defect

David A , Srirangalingam U , Metherell LA , Khoo B , Clark AJL

Background: The growth hormone receptor (GHR) 6Ψ pseudoexon mutation (A to G at ds-1) is one of the most frequent mutations causing GH insensitivity. It causes aberrant mRNA splicing, leading to activation of a pseudoexon and insertion of 36 additional amino acids, resulting in a functionless receptor. Although IGF-I remains the mainstay of treatment for these patients we investigated the ability of RNA antisense oligonucleotides (ASOs) to correct aberrant GHR splicing us...

ea0011oc4 | Signal transduction OC1 Novartis Oncology Young Investigator Award | ECE2006

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

Cooray SN , Chapple JP , Metherell LA , Cheetham ME , Clark AJL

Familial Glucocorticoid Deficiency type 2 (patients with normal MC2R) is associated with mutations in the MRAP (Melanocortin Receptor Accessory Protein) gene. In order to investigate the function of this novel single transmembrane domain protein, CHO and SKN-SH cells were transfected with MRAP-FLAG and/or MC2R-GFP constructs and imaged using confocal microscopy. Although the MC2R-GFP failed to be expressed at the cell surface when transfected alone, it was found to be expresse...

ea0011p574 | Growth and development | ECE2006

Prolonged expression of the ACTH receptor, MC2-R, during 3T3-L1 adipocyte differentiation is dependent upon switching promoter usage to an adipocyte-specific, C/EBP-driven, downstream promoter

Noon LA , Clark AJL , O’Shaughnessy PJ , King PJ

The peptide hormone ACTH stimulates lipolysis and suppresses leptin production in adipocytes via the G-protein coupled seven transmembrane receptor, MC2-R. We have shown previously that PPARγ2 is the primary factor responsible for transactivation of the already identified murine MC2-R promoter in the differentiating 3T3-L1 adipocyte cell line. In this study we show that despite the activity of this promoter being transient during differentiation, MC2-R mRNA remains elevat...

ea0065p48 | Adrenal and Cardiovascular | SFEBES2019

Twenty-five years of familial glucocorticoid deficiency: genotypic and phenotypic variability

Smith CJ , Maharaj AV , Prasad R , Hughes C , Qamar Y , Clark AJL , Chan LF , Metherell LA

Within the last 25 years more than 400 cases with suspected Familial Glucocorticoid Deficiency (FGD) have been referred to our centre for genetic testing. All cases had low or undetectable serum cortisol paired with an elevated plasma ACTH level. Our patient cohort comprises 352 families from 30 different nationalities and ranges from neonates to patients in their eighties. In 1993 the first gene defect, in MC2R, was discovered by candidate gene sequencing. Subsequent...

ea0011p754 | Steroids | ECE2006

Novel mutations in the ACTH receptor gene as a cause of familial glucocorticoid deficiency

Chan LF , Metherell LA , Krude H , Carel JC , DeLamater PV , Huebner A , Clark AJL

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease resulting from adrenal unresponsiveness to ACTH. Patients present in early childhood with hyperpigmentation, hypoglycaemic episodes and seizures secondary to glucocorticoid deficiency. If left untreated this condition is fatal. Mineralocorticoid production is normal. Mutations in the ACTH receptor have been well described and account for approximately 25% of cases. We describe 3 additional novel mut...

ea0011oc42 | Endocrine genetics | ECE2006

Linkage of a fourth gene for familial glucocorticoid deficiency to chromosome 13q

Metherell LA , Becker C , Ruschendorf F , Naville D , Begeot M , Nurnberg P , Huebner A , Savage MO , Clark AJL

Expression of the ACTH receptor (MC2R), a 7 transmembrane GPCR, has been difficult to achieve in cell lines that are not of adrenal origin. Heterologous expression of this gene in many cell lines (CHO, Hela, H295R, HEK293) produces a protein that is trapped in the ER, suggesting that an accessory factor(s) might be necessary to traffic MC2R through the cell. We recently identified such an accessory factor, MRAP that rescues MC2R expression in some, but not all, cell lines. Mut...

ea0008p83 | Steroids | SFE2004

Familial Glucocorticoid Deficiency type 2 is associated with mutations in a novel gene encoding a small single transmembrane domain protein

Metherell LA , Chapple JP , Cooray S , Becker C , Begeot M , Naville D , Nurnberg P , Huebner A , Cheetham ME , Clark AJL

Familial Glucocorticoid Deficiency (FGD) [OMIM #202200] is an autosomal recessive disorder resulting from resistance to the action of adrenocorticotropin (ACTH) on the adrenal cortex to stimulate glucocorticoid production. It has previously been linked to mutations in the ACTH receptor (ACTHR) [FGD type 1] and a locus on chromosome 8q, but 70% of cases have no known cause. The aim of this study was to identify additional loci and genes for FGD using a linkage mapping strategy....