Human leptin deficiency caused by a missense mutation: Multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicatenew targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects

We have previously demonstrated that genetically based leptin deficiency du e to a missense leptin gene mutation in a highly consanguineous extended Tu rkish pedigree is associated with morbid obesity and hypogonadism. We have now performed detailed assessments of endocrine, sympathetic, and immune fu nction. We have also identified a new adult female homozygous patient in th is extended family who is severely obese and amenorrheic. In this family al l wild-type and heterozygous individuals have normal body weight. Seven obe se members of this family, whom we presume to have been leptin deficient, d ied during childhood. There are several findings that indicate potentially novel targets for leptin action in humans. Four homozygous patients (1 adul t male, 2 adult females, and 1 child) have sympathetic system dysfunction, whereas all heterozygous subjects have normal sympathetic system function. Despite sympathetic system dysfunction and postural hypotension, 1 of 3 hom ozygous adult patients has impaired renin-aldosterone function. The patient s also exhibit alterations in GH and PTH-calcium function, and 1 of them ha s decreased bone mineral density. Despite their obesity, these patients do not have risk factors for cardiovascular disease, such as hypertension, imp airments in lipid metabolism, or hyperglycemia. These data support the hypo thesis that the obese may have central, but not peripheral, resistance to t he effects of leptin and that hyperglycemia may mediate the cardiovascular morbidity of the obese who are not leptin deficient. Furthermore, these dat a indicate that there may be several new targets for leptin action in human physiology. Such new targets may lead to novel pharmacological strategies for the use of leptin agonists and antagonists in the treatment of human di sease. All 19 normal weight individuals in this family are alive, whereas 7 of 11 obese individuals died in childhood after infections. The odds ratio for mortality in the context of this obesity phenotype is 25.4, indicating that this mutation severely impairs key biological functions during childh ood, negatively impacting on survival. We found that only the obese child i n this family had thyroid function abnormalities. The oldest homozygous fem ale patient started to menstruate, albeit with a luteal phase defect, 7 mon ths ago, after a delay of over 20 yr, whereas the younger adult subjects ar e still hypogonadic. Thus, we conclude that due to their long life span, hu mans who survive the negative effects of leptin deficiency during childhood can, in contrast to ob/ob mice, over decades compensate some of the effect s of leptin deficiency on immunity and endocrine function through mechanism s that remain to be elucidated.