CONTEXT: Genetic variants affecting the nuclear hormone receptor coactivator Steroid Receptor Coactivator, SRC-1, have been identified in people with severe obesity and impair melanocortin signaling in cells and mice. As a result, obese patients with SRC-1 deficiency are being treated with a Melanocortin 4 receptor agonist in clinical trials. OBJECTIVE: Here, our aim was to comprehensively describe and characterise the clinical phenotype of SRC-1 variant carriers to facilitate diagnosis and clinical management. DESIGN: In genetic studies of 2,462 people with severe obesity, we identified 23 rare heterozygous variants in SRC-1. We studied 29 adults and 18 children who were SRC-1 variant carriers and performed measurements of metabolic and endocrine function, liver imaging and adipose tissue biopsies. Findings in adult SRC-1 variant carriers were compared to 30 age and BMI-matched controls. RESULTS: The clinical spectrum of SRC-1 variant carriers included increased food intake in children, normal basal metabolic rate, multiple fractures with minimal trauma (40%), persistent diarrhea, partial thyroid hormone resistance and menorrhagia. Compared to age, sex and BMI matched controls, adult SRC-1 variant carriers had more severe adipose tissue fibrosis (46.2% v 7.1% respectively, P=0.03) and a suggestion of increased liver fibrosis (5/13 cases versus 2/13 in controls, odds ratio 3.4), although this was not statistically significant. CONCLUSIONS: SRC-1 variant carriers exhibit hyperphagia in childhood, severe obesity and clinical features of partial hormone resistance. The presence of adipose tissue fibrosis and hepatic fibrosis in young patients suggests that close monitoring for the early development of obesity-associated metabolic complications is warranted.
J Clin Endocrinol Metab
SRC-1, hormone resistance, nuclear hormone receptors, obesity