In humans, a loss-of-function mutation in FTO leads to an even more complex phenotype of postnatal growth retardation, microcephaly, severe psychomotor delay, functional brain deficits, and characteristic facial dysmorphism.159 In some patients, structural brain malformations, cardiac defects, genital anomalies, and cleft palate were also observed. The R316Q mutation, which disrupts one of the obligate arginines necessary for 2-OG binding, results in loss of FTO’s demethylase activity. The importance of FTO’s ability to demethylate is underlined not only by the severe phenotype detailed above, but also by the tragic fact that none of the affected individuals survived past the age of 30 months.159 So in both humans and mice, a fully functional FTO certainly appears to be critical for normal physiology.
