Brain-derived neurotrophic factor and obesity in the WAGR syndrome

Abstract

Background: Brain-derived neurotrophic factor (BDNF) has been found to be important in energy homeostasis in animal models, but little is known about its role in energy balance in humans. Heterozygous, variably sized, contiguous gene deletions causing haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13, approximately 4 Mb centromeric to BDNF (11p14.1), result in the Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome. Hyperphagia and obesity were observed in a subgroup of patients with the WAGR syndrome. We hypothesized that the subphenotype of obesity in the WAGR syndrome is attributable to deletions that induce haploinsufficiency of BDNF.

Methods: We studied the relationship between genotype and body-mass index (BMI) in 33 patients with the WAGR syndrome who were recruited through the International WAGR Syndrome Association. The extent of each deletion was determined with the use of oligonucleotide comparative genomic hybridization.

Results: Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions. These patients had significantly higher BMI z scores throughout childhood than did patients with intact BDNF (mean [+/-SD] z score at 8 to 10 years of age, 2.08+/-0.45 in patients with heterozygous BDNF deletions vs. 0.88+/-1.28 in patients without BDNF deletions; P=0.03). By 10 years of age, 100% of the patients with heterozygous BDNF deletions (95% confidence interval [CI], 77 to 100) were obese (BMI > or = 95th percentile for age and sex) as compared with 20% of persons without BDNF deletions (95% CI, 3 to 56; P<0.001). The critical region for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF. Serum BDNF concentrations were approximately 50% lower among the patients with heterozygous BDNF deletions (P=0.001).

Conclusions: Among persons with the WAGR syndrome, BDNF haploinsufficiency is associated with lower levels of serum BDNF and with childhood-onset obesity; thus, BDNF may be important for energy homeostasis in humans.

Figure 1. Genetic Loci on Chromosome 11, Body-Mass Index, Hyperphagia, and Concentrations of Serum BDNF in Patients with the WAGR Syndrome

As shown in Panel A, the WAGR syndrome is caused by deletions on chromosome 11p that result in haploinsufficiency for the PAX6 and WT1 genes. BDNF is located approximately 4 Mb telomeric to PAX6. Panel B shows body-mass index (BMI) z scores in patients 20 years of age or younger, adjusted for the BMI of the mother and father, in patients with BDNF haploinsufficiency (BDNF+/−) and patients with intact BDNF (BDNF+/+). Anthropometric data were obtained from medical records. The sample size for each age range is shown. Values are means ±SE. Nominal P values are shown. Panel C shows the scores for types of behavior, the drive to eat, and severity of symptoms from the hyperphagia questionnaire in patients with BDNF haploinsufficiency (BDNF+/−) and patients with intact BDNF (BDNF+/+). The minimum total score for this questionnaire is 11, and the maximum total score is 55 with higher scores indicating greater hyperphagia. Subtotal and total scores are shown as means ±SE. Panel D shows that the concentration of serum BDNF was significantly lower in patients with BDNF haploinsufficiency (BDNF+/−) than in patients with intact BDNF (BDNF+/+). Individual values are shown, and horizontal bars indicate group means.

Figure 2. Body-Mass Index According to Age in Two Subjects

The percentiles for body-mass index (BMI) according to age in a female subject with BDNF haploinsufficiency (Subject 10 in Appendix 6 in the Supplementary Appendix; BDNF+/−) and a female subject with intact BDNF (Subject 31 in Appendix 6 in the Supplementary Appendix; BDNF+/+) are shown in this standard growth chart for girls, from the Centers for Disease Control and Prevention. These patients had deletions of similar size (approximately 13 Mb) but divergent BMI values.

Figure 3. Regions of Deletion on Chromosome 11p

The region of deletion on chromosome 11p is shown for each of the 24 patients in whom the presence or absence of childhood obesity (body-mass index [BMI] ≥95th percentile by 10 years of age) could be determined. No association between the centromeric deletion boundary and childhood obesity was observed. However, for the telomeric deletion boundary, all patients with heterozygous deletion of all or a portion of BDNF had childhood obesity, whereas no deletions involved BDNF in the patients who were of normal weight. In Patient 1, who was obese, there was a heterozygous deletion of BDNF exons 1 through 3. In Patient 2, who had a normal weight (BMI, approximately 20th percentile at 10 years of age), the deletion region ended 72.5 kb upstream of BDNF. Only 20% of the patients without BDNF deletions were obese; this rate is similar to the prevalence of childhood obesity in the general U.S. population.