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A correction has been published: N Engl J Med 2008;359(13):1414.
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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
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.
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).
Source Information
From the Unit on Growth and Obesity, Program in Developmental Endocrinology and Genetics (J.C.H., R.L.L., C.M.M., K.S.J.-G., D.C.A.-W., E.L.S., J.A.Y.), and the Laboratory of Clinical Genomics (O.M.R.), Eunice Kennedy Shriver National Institute of Child Health and Human Development; and the Genome Technology Branch (M.J.) and the Medical Genetics Branch (F.L.L.), National Human Genome Research Institute, National Institutes of Health — all in Bethesda, MD; and the Molecular Neurobiology Branch, National Institute of Drug Abuse, Baltimore (Q.-R.L., G.R.U.).
Address reprint requests to Dr. Yanovski at the Unit on Growth and Obesity, National Institutes of Health, 10 Center Dr., Hatfield Clinical Research Center, Rm. 1E-3330, MSC 1103, Bethesda, MD 20892-1103, or at jy15i{at}nih.gov.
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