Final published version
Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability
AU - Kasher, Paul R.
AU - Shertz, Katherine E.
AU - Thomas, Megan
AU - Jackson, Adam
AU - Annunziata, Silvia
AU - Ballesta-Martinez, Maria J.
AU - Campeau, Philippe M.
AU - Clayton, Peter E.
AU - Eaton, Jennifer L.
AU - Granata, Tiziana
AU - Guille-Navarro, Encarna
AU - Hernando, Cristina
AU - Laverriere, Caroline E.
AU - Lieden, Agne
AU - Villa-Marcos, Olaya
AU - McEntagart, Meriel
AU - Nordgren, Ann
AU - Pantaleonie, Chiara
AU - Prebel-Richard, Celine
AU - Sarret, Catherine
AU - Sciacca, Francesca L.
AU - Wright, Ronnie
AU - Kerr, Bronwyn
AU - Glasgow, Eric
AU - Banka, Siddharth
PY - 2016/2/4
Y1 - 2016/2/4
N2 - 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.
AB - 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.
KW - obesity
KW - intellectual disability
KW - POU3F2 (also called BRN2 or N-OCT3 or OCT7)
KW - 6q16
KW - SIM1
KW - oxytocin
U2 - 10.1016/j.ajhg.2015.12.014
DO - 10.1016/j.ajhg.2015.12.014
M3 - Journal article
VL - 98
SP - 363
EP - 372
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -