Discovery of an obesity susceptibility gene, KSR2, provides new insight into energy homeostasis pathways.

Abstract

Obesity is a heterogeneous condition with considerable heritability. Multiple adiposity genes have now been identified through genome-wide association studies and studies of rare forms obesity caused by single-gene mutations. Several of these monogenic forms of obesity seem to replicate mouse obesity phenotypes, with notable examples including obesity caused by inactivating mutations in leptin, the leptin receptor, and the melanocortin-4 receptor. A large-scale screen for additional obese phenotypes in mice found that targeted deletion of Ksr2 leads to obesity,1 suggesting a role for Ksr2 in energy homeostasis. Ksr2 encodes the scaffolding protein kinase suppressor of ras 2 (KSR2), which may regulate multiple signaling pathways by binding kinases, such as Raf and AMP-activated protein kinase (AMPK). In this article, Pearce et al2 hypothesize that genetic variants in KSR2 may contribute to the development of severe, early onset obesity in humans. Using a combination of Sanger and whole-exome sequencing, the authors sequenced the coding region and intron/exon boundaries of KSR2 to identify rare variants (minor allele frequency, <0.5%) in 2101 individuals of mixed European ancestry who developed severe obesity before 10 years and in 1536 controls from a UK population-based study. They also performed a small replication study (238 cases and 1117 controls) and sequenced KSR2 in family members of severely obese probands to determine whether KSR2 variants cosegregated with overweight/obesity …