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Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability

Research output: Contribution to journalJournal article

  • Paul R. Kasher
  • Katherine E. Shertz
  • Megan Thomas
  • Adam Jackson
  • Silvia Annunziata
  • Maria J. Ballesta-Martinez
  • Philippe M. Campeau
  • Peter E. Clayton
  • Jennifer L. Eaton
  • Tiziana Granata
  • Encarna Guille-Navarro
  • Cristina Hernando
  • Caroline E. Laverriere
  • Agne Lieden
  • Olaya Villa-Marcos
  • Meriel McEntagart
  • Ann Nordgren
  • Chiara Pantaleonie
  • Celine Prebel-Richard
  • Catherine Sarret
  • And 5 others
  • Francesca L. Sciacca
  • Ronnie Wright
  • Bronwyn Kerr
  • Eric Glasgow
  • Siddharth Banka
<mark>Journal publication date</mark>4/02/2016
<mark>Journal</mark>American Journal of Human Genetics
Issue number2
Number of pages10
Pages (from-to)363-372
Publication statusPublished
Early online date28/01/16
Original languageEnglish


Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ∼350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.