Obesity Due to Steroid Receptor Coactivator-1 Deficiency Is Associated With Endocrine and Metabolic Abnormalities

Abstract

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.

Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management

“…Variants in ≥1 gene and/or chromosomal deletion with a strong effect [ 56 , [85] , [86] , [87] , [88] , [89] , [90] ]…”

Syndromic and Monogenic Obesity: New Opportunities Due to Genetic-Based Pharmacological Treatment

“…Steroid receptor coactivator-1 (SRC1) affects the expression of many target genes [52]. In a previous large exome-sequencing study of patients with severe obesity, rare heterozygous variants in SRC1 were detected and were associated with the dysregulation of POMC expression [53,54]. Importantly, SRC-1 deletion also caused obesity in mice [55].…”

“…In a recent study, it was shown that in the hypothalamus, SRC-1 interacts with phosphorylated signal transducer and activator of transcription-3 (STAT3), affecting POMC expression [56]. Patients with SRC1 mutations and severe obesity have been enrolled in phase 2 clinical trials of setmelanotide, an MC4R agonist, approved for obese patients with POMC or LEPR mutations [54].…”

Current Treatments for Patients with Genetic Obesity

“…Other genes are also implicated in the regulation of this pathway including MRAP2 encoding for the melanocortin receptor accessory protein 2 ( 8 , 9 ), ADCY3 encoding for adenylate cyclase 3 which transmits the MC4R activation signal intracellularly ( 10 ). Several genes involved in development of the hypothalamus or MC4R regulation have been reported to influence this signaling, including semaphorin 3A-G ( SEMA3A-G), plexinA1–4 ( PLXNA1–4 ), neuropilin1–2 ( NRP1–2 ) ( 11 ), kinase suppressor of ras 2 ( KSR2 ) ( 12 ), and the steroid-receptor co-activator 1 ( SRC-1 ) ( 13 ). Genetic alterations in these genes lead to the phenotype described in both monogenic obesity and also in syndromic obesity.…”