Endocrine Abstracts

It is ten years since we identified the human melanocortin 1 receptor (MC1R) as the locus that underpins red hair, freckling and sun sensitivity. The MC1R is not the only gene that is important in human pigmentation, but it does seem to play a significant role. A striking aspect of the MC1R is the degree of genetic diversity. I review how a combination of laboratory and genetic epidemiological studies has shown how a single locus, that in some instances behaves c...

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...

The anorexigenic hormone leptin seems to be the principal adiposity indicator and signal of the state of nutrition, as its plasma levels are highly correlated to adipocyte number and fat content. The elucidation of the causes of monogenic forms of obesity has benefited from the positional cloning of a series of mouse obesity genes, including those that encode leptin, the leptin receptor (LEPR). Targeted genetic manipulation has also established the vital regulatory role of mol...

Melanocortin receptors (MCR), which belong to the superfamiliy of G protein-coupled receptors (GPCR), are preferentially coupled to Gs proteins and play a major role in the regulation of energy homeostasis. In line with this notion, mutations in the MC4R gene are the most frequent monogenic cause of severe obesity in human beings. Surprisingly, MC4R mutations isolated from obese candidates showed both increased or decreased potency to promote the Gs signalling pathway when ove...