We have been conducting a comprehensive genotype-phenotype correlation study in patients with the WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome, which is caused by heterozygous contiguous gene deletions of variable size in the chromosome 11p13 region. We had previously observed that haploinsufficiency for BDNF, the gene which encodes brain-derived neurotrophic factor, is associated with higher prevalence of childhood obesity and higher scores on a hyperphagia questionnaire. BDNF is widely expressed throughout the nervous system and plays an important role in neuronal development and synaptic plasticity. In animal studies, BDNF appears to function downstream of the leptin signaling pathway to regulate appetite and energy balance. Our findings support the role of BDNF in human energy homeostasis. We have been conducting further studies to characterize the role of BDNF in neurocognitive function because Bdnf+/- mice are not only hyperphagic and obese, but also display learning deficits, behavioral abnormalities, and decreased thermal pain response. In a cohort of 31 patients with the WAGR syndrome, we observed that BDNF haploinsufficiency was associated with lower scores on a parent-completed questionnaire assessing behavior responses to injuries or illnesses considered painful to most people (p=0.03). These findings suggest that BDNF plays a role in human nociception. Studies are currently underway to examine detection and pain thresholds for hot and cold stimuli. Tests of cognitive and adaptive function, psychiatric symptoms, and autism spectrum diagnoses are also ongoing. A treatment study using a BDNF agonist in patients with BDNF haploinsufficiency is also under development. We have also been studying patients with Prader-Willi syndrome (PWS), which is caused by a lack of paternally expressed genes on chromosome 15q11-13. Patients with PWS typically present with hypotonia and poor feeding in the neonatal period followed by marked weight gain and severe hyperphagia between the ages of 1-5 years. PWS is also associated with cognitive impairment and behavioral abnormalities. We conducted a pilot study comparing 13 children with PWS versus 13 age/sex-matched lean controls and 13 age/sex/body mass index (BMI)-matched obese controls. We observed that patients with PWS had lower serum BDNF compared to the lean controls (p=0.03) as well as the obese controls (p=0.01). Lower serum BDNF suggests insufficient central nervous system production of BDNF because BDNF in peripheral circulation is believed to reflect cerebral output of BDNF. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. BDNF insufficiency may also contribute to the neurocognitive abnormalities observed in PWS. We are currently conducting a study in a larger cohort of patients with PWS (25 infants, 25 non-obese children, and 25 obese children) and 75 BMI-matched controls to confirm these findings and to examine possible associations between cognitive function and serum BDNF concentrations. In addition, we are investigating the role of BDNF in other conditions associated with childhood obesity (e.g. melanocortin 4-receptor mutations) and/or neurocognitive impairment (e.g. autism spectrum disorders - in collaboration with Dr. Swedos research group). We are also studying the role of single nucleotide polymorphisms of the BDNF gene locus in body weight regulation and cognitive function in healthy adults and children. In collaboration with Dr. Kleinmans research group, we are examining the associations of BDNF genotype with BMI and hypothalamic BDNF expression in cadaveric brain tissue from adults with sudden death. In collaboration with Dr. Bieseckers research group, we have been studying patients with Bardet-Biedl syndrome (BBS), a cilopathy associated with obesity. In animal models of cilia dysfunction, defects in leptin receptor trafficking and signaling have been reported. In our human studies, we have observed that patients with BBS (n=50) have nearly two-fold higher serum leptin concentrations (p<0.001) compared with age/sex/race/BMI-matched control subjects (n=100). Hyperleptinemia out of proportion to degree of adiposity suggests that leptin resistance may be the causative etiology of obesity in BBS. We are currently seeking to replicate this observation in patients with Alstrom syndrome, a disorder that is distinct from BBS but is also associated with cilia dysfunction.

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Hanish, Alyson E; Han, Joan C (2018) Delayed Onset of Sleep in Adolescents With PAX6 Haploinsufficiency. Biol Res Nurs 20:237-243
Han, Joan C; Reyes-Capo, Daniela P; Liu, Chia-Ying et al. (2018) Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls. J Clin Endocrinol Metab 103:2707-2719
Hanish, Alyson E; Lin-Dyken, Deborah C; Han, Joan C (2017) PROMIS Sleep Disturbance and Sleep-Related Impairment in Adolescents: Examining Psychometrics Using Self-Report and Actigraphy. Nurs Res 66:246-251
Hanish, Alyson E; Butman, John A; Thomas, Francine et al. (2016) Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency. J Sleep Res 25:16-22
Heymsfield, Steven B; Avena, Nicole M; Baier, Leslie et al. (2014) Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia. Obesity (Silver Spring) 22 Suppl 1:S1-S17
Hohenadel, M G; Thearle, M S; Grice, B A et al. (2014) Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants. Int J Obes (Lond) 38:1068-74
Gill, Richard; Cheung, Yee Him; Shen, Yufeng et al. (2014) Whole-exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity. Obesity (Silver Spring) 22:576-84
Drgonova, Jana; Jacobsson, Josefin A; Han, Joan C et al. (2013) Involvement of the neutral amino acid transporter SLC6A15 and leucine in obesity-related phenotypes. PLoS One 8:e68245
Han, Joan C; Thurm, Audrey; Golden Williams, Christine et al. (2013) Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. Cortex 49:2700-10
Sherafat-Kazemzadeh, R; Ivey, L; Kahn, S R et al. (2013) Hyperphagia among patients with Bardet-Biedl syndrome. Pediatr Obes 8:e64-7

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