Nishigori et al. (2001) identified mutations in the NR0B2 gene (604630) that segregated with mild or moderate early-onset obesity in Japanese subjects.
Dubern et al. (2001) searched for mutations in the genes encoding the melanocortin-4 receptor ... Nishigori et al. (2001) identified mutations in the NR0B2 gene (604630) that segregated with mild or moderate early-onset obesity in Japanese subjects. Dubern et al. (2001) searched for mutations in the genes encoding the melanocortin-4 receptor (MC4R; 155541), alpha-MSH (see 176830), and agouti-related protein (602311) in 63 severely obese children. Four dominantly inherited heterozygous missense MC4R mutations were identified in 4 unrelated children and none of the control subjects. Expression of the obese phenotype was variable in mutation-positive family members. Dubern et al. (2001) concluded that MC4R mutations may be a nonnegligible cause of severe obesity in children with variable expression and penetrance. In 24 (5.1%) of 469 severely obese white subjects (370 women and 99 men) and 1 (4%) of 25 normal-weight controls (15 women and 10 men), Branson et al. (2003) identified mutations in the MC4R gene. All mutation carriers reported binge eating, as compared with 14.2% of obese subjects without mutations and none of the normal-weight subjects without mutations. The prevalence of binge eating was similar among carriers of mutations in the leptin-binding domain of LEPR and noncarriers. List and Habener (2003) commented on the possible importance of ethnic background in the frequency of mutations in MC4R in obesity. They also suggested that the findings of Branson et al. (2003) be interpreted with caution, as they differed from earlier findings of a binge-eating disorder prevalence of 5% among carriers of MC4R mutations (Sina et al., 1999). Hebebrand et al. (2004) compared the eating behavior of 43 obese probands with functionally relevant MC4R mutations to wildtype controls. No significant differences in binge-eating episodes between carriers of the MC4R variants and wildtype controls were detected, and Hebebrand et al. (2004) concluded that binge-eating episodes are not a distinct feature of MC4R mutation carriers. This analysis was different from the study of Branson et al. (2003) because Hebebrand et al. (2004) studied only carriers of mutations that had been shown to be of functional relevance in vitro and did not include carriers of silent variants in the open reading frame, variants in UTRs, or the val103-to-ile (V103I) or ile251-to-leu (I251L) polymorphisms. In 29 (5.8%) of 500 probands with severe childhood obesity, Farooqi et al. (2003) identified mutations in the MC4R gene (155541.0010-155541.0019). To identify potential genetic contributors to the quantitative trait body weight, Ahituv et al. (2007) resequenced coding exons and splice junctions of 58 genes in 379 obese and 378 lean individuals. This 96-Mb survey included 21 genes associated with monogenic forms of obesity in human or mice, as well as 37 genes that function in body weight-related pathways. They found that the monogenic obesity-associated gene group was enriched for rare nonsynonymous variants unique to the obese population compared with the lean population. In addition, computational analysis predicted a greater fraction of deleterious variants within the obese cohort. Together, these data suggested that multiple rare alleles contribute to obesity in the population and provide a medical sequencing-based approach to detecting them. The accumulation of mildly deleterious missense mutations in individual human genomes is proposed as a genetic basis for complex diseases. The plausibility of this hypothesis depends on quantitative estimates of the prevalence of mildly deleterious de novo mutations and polymorphic variants in humans and on the intensity of selective pressure against them. Kryukov et al. (2007) combined analysis of mutations causing human mendelian diseases as cataloged in the Human Genome Mutation Database (HGMD) (Stenson et al., 2003) with analysis of human-chimpanzee divergence and systematic data on human genetic variation and found that approximately 20% of new missense mutations in humans result in a loss of function, whereas approximately 27% are effectively neutral. Thus the remaining 53% of new missense mutations have mildly deleterious effects. These mutations give rise to many low-frequency deleterious allelic variants in the human population, as is evident from a new dataset of 37 genes sequenced in more than 1,500 individual human chromosomes. Up to 70% of low frequency missense alleles are mildly deleterious and are associated with a heterozygous fitness loss in the range of 0.001-0.003. Thus, the low allele frequency of an amino acid variant can, by itself, serve as a predictor of its functional significance. The observation that the majority of human rare nonsynonymous variants are deleterious, and thus are of significance to function and phenotype, suggests a strategy for candidate gene association studies. Disease populations are expected to have a higher rate of rare amino acid variants in genes involved in disease than are healthy control populations. This difference can be easily detected in a deep resequencing study. Obviously, this strategy would be highly inefficient if the majority of coding variants at low frequency were neutral. Kryukov et al. (2007) concluded that their analysis provides an explanation for the success of studies, such as the one of Ahituv et al. (2007), which demonstrate an excess of rare missense variants in individuals with phenotypes associated with disease risk. A heterozygous missense mutation in the POMC gene (173830.0004) was associated with severe childhood obesity in 2 unrelated children and segregated with obesity in the 3-generation family of 1 of the children. A heterozygous missense mutation in the CART gene (602606.0001) was associated with obesity in a 3-generation Italian family. Willer et al. (2009) performed a metaanalysis of 15 genomewide association studies for BMI comprising 32,387 participants and followed up top signals in 14 additional cohorts comprising 59,082 participants. They strongly confirmed association with FTO and MC4R and identified 6 additional loci (P less than 5 x 10(-8)): TMEM18 (613220), KCTD15 (615240), GNPDA2 (613222), SH2B1 (608937), MTCH2 (613221), and NEGR1 (613173) (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the CNS, emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.