Following the identification of the leptin gene mutation in ob/ob mice, three highly obese children from two consanguineous but unrelated families who carried non-functioning mutations of the leptin gene were identified from a study population characterized by extreme obesity.
The defect in both pedigrees was a homozygous deletion of a single guanine nucleotide at codon 133 of the leptin gene which resulted in a frameshift mutation and truncated protein (Montague et al., 1997).
Although immunoreactive leptin concentrations are typically increased rather than decreased in obesity suggesting that this defect per se is certainly not a common cause of obesity in the general population, this discovery led to intensification of the search amongst other forms of both syndromic and non-syndromic forms of obesity for other candidate genes.
Mutations of six genes have been characterized in human forms of monogenic obesity (Table 2.1).
It is noteworthy that five of these six human monogenic obesity genes encode proteins involved in the leptin pathway of appetite regulation (see Figure 2.1).
Whether this is because this pathway is the dominant pathway of weight regulation, or whether it results from poor understanding of alternative regulatory pathways is not yet clear.
Warden CH and Fisler JS
Katsanis N, Beales PL, Woods MO