Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor

Abstract

Background: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined.

Methods: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives.

Results: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency.

Conclusions: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.

Figure 1. Mutations in the Leptin-Receptor Gene (Panel A) and in Vitro Function of the Leptin-Receptor Mutant Constructs (Panel B)

Panel A shows the positions of the identified mutations in the leptin receptor. We observed homozygous mutations in seven severely obese probands; in an eighth (Subject 1 in Family 8, a compound heterozygote), we observed a nonsense mutation and a missense mutation (asterisks). Amino acid numbers are shown on the left-hand side. Panel B shows the induction of the phosphorylation of signal transducer and activator of transcription 3 (STAT3) by wild-type and mutant leptin receptors in the absence (minus signs) and presence (plus signs) of recombinant human leptin. The control construct was an empty pcDNA3 vector.

Figure 2. Pedigrees of Consanguineous Families and Nonconsanguineous Families with Mutations in the Leptin-Receptor Gene That Segregate with Severe Obesity

The squares represent male family members, and the circles female family members; open symbols represent unaffected family members, and solid symbols family members with obesity (in adults, defined as a BMI [the weight in kilograms divided by the square of the height in meters] of 30 or more; in children, defined as a BMI above the 99th age-adjusted percentile). A slash through the symbol denotes a subject who has died. Below each symbol, age is given, followed by the BMI value, the BMI standard-deviation score, and the genotype, with N denoting the normal (wild-type) allele and M the mutant allele. In Family 8, M_f denotes the frame-shift mutation, and M_m the missense mutation. For subjects in whom it was available, the percentage of body fat, measured by dual-energy x-ray absorptiometry, is listed below the genotype.

Figure 3. Body-Mass Index (BMI) (Panel A), Percentage of Body Fat (Panel B), Ad Libitum Energy Intake (Panel C), and Serum Leptin Levels (Panel D) in Leptin-Receptor Deficiency

Panel A shows the BMI standard-deviation score. Panel B shows the percentage of body fat as measured by dual-energy x-ray absorptiometry. Panel C shows the ad libitum energy intake at a test meal (adjusted for kilograms of lean mass). In Panel D, the horizontal line indicates the geometric mean. The data in Panels A, B, and C are means ±SD. Subjects 1, 2, and 3 in Family 4 were not able to travel to the United Kingdom, so data for 7 (rather than 10) subjects who were homozygous for LEPR mutations are presented in Panels B and C. The BMI is calculated as the weight in kilograms divided by the square of the height in meters. MC4R denotes melanocortin 4 receptor.