There are several examples where common variants close to a particular gene, such as MCR4,11,146-148 POMC,149,150 BDNF,13,151 and PCSK1,152,153 are associated with alterations in risk of common phenotypes such as fat mass or risk of obesity, whereas rare loss-of-function mutations in these same genes result in highly penetrant severe early onset obesity. FTO however, has proven to be far more complicated. Fto was originally identified as one of six contiguous genes in a 1.6Mb deletion causing the ‘fused-toe’ phenotype.154 This deletion included not only FTO, but also Ftm, Ftl and the Iroquois B cluster consisting of Irx3, 5, and 6. Homozygotes are embryonically lethal, while heterozygous fused toes mutants display severe developmental defects including left-right asymmetry,155 defects in hypothalamic development,155,156 as well as fused digits and hyperplasia of the thymus without any metabolic alterations. In contrast, mice with a specific targeted deletion of Fto did not display these severe developmental abnormalities, but exhibited a phenotype of postnatal growth retardation, decreased fat and lean body mass, and elevated food intake when corrected for lean body mass.157 There was also a significant level of post-natal lethality, with only 50% of homozygous pups reaching weaning age.157,158
