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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 Journal/Magazine › Journal article › peer-review

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Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability. / Kasher, Paul R.; Shertz, Katherine E.; Thomas, Megan et al.
In: American Journal of Human Genetics, Vol. 98, No. 2, 04.02.2016, p. 363-372.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Kasher, PR, Shertz, KE, Thomas, M, Jackson, A, Annunziata, S, Ballesta-Martinez, MJ, Campeau, PM, Clayton, PE, Eaton, JL, Granata, T, Guille-Navarro, E, Hernando, C, Laverriere, CE, Lieden, A, Villa-Marcos, O, McEntagart, M, Nordgren, A, Pantaleonie, C, Prebel-Richard, C, Sarret, C, Sciacca, FL, Wright, R, Kerr, B, Glasgow, E & Banka, S 2016, 'Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability', American Journal of Human Genetics, vol. 98, no. 2, pp. 363-372. https://doi.org/10.1016/j.ajhg.2015.12.014

APA

Kasher, P. R., Shertz, K. E., Thomas, M., Jackson, A., Annunziata, S., Ballesta-Martinez, M. J., Campeau, P. M., Clayton, P. E., Eaton, J. L., Granata, T., Guille-Navarro, E., Hernando, C., Laverriere, C. E., Lieden, A., Villa-Marcos, O., McEntagart, M., Nordgren, A., Pantaleonie, C., Prebel-Richard, C., ... Banka, S. (2016). Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability. American Journal of Human Genetics, 98(2), 363-372. https://doi.org/10.1016/j.ajhg.2015.12.014

Vancouver

Kasher PR, Shertz KE, Thomas M, Jackson A, Annunziata S, Ballesta-Martinez MJ et al. Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability. American Journal of Human Genetics. 2016 Feb 4;98(2):363-372. Epub 2016 Jan 28. doi: 10.1016/j.ajhg.2015.12.014

Author

Kasher, Paul R. ; Shertz, Katherine E. ; Thomas, Megan et al. / Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 2. pp. 363-372.

Bibtex

@article{aee1ac4c6b9243f99f1423a0b494bedd,
title = "Small 6q16.1 deletions encompassing POU3F2 cause susceptibility to obesity and variable developmental delay with intellectual disability",
abstract = "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.",
keywords = "obesity, intellectual disability, POU3F2 (also called BRN2 or N-OCT3 or OCT7), 6q16, SIM1, oxytocin",
author = "Kasher, {Paul R.} and Shertz, {Katherine E.} and Megan Thomas and Adam Jackson and Silvia Annunziata and Ballesta-Martinez, {Maria J.} and Campeau, {Philippe M.} and Clayton, {Peter E.} and Eaton, {Jennifer L.} and Tiziana Granata and Encarna Guille-Navarro and Cristina Hernando and Laverriere, {Caroline E.} and Agne Lieden and Olaya Villa-Marcos and Meriel McEntagart and Ann Nordgren and Chiara Pantaleonie and Celine Prebel-Richard and Catherine Sarret and Sciacca, {Francesca L.} and Ronnie Wright and Bronwyn Kerr and Eric Glasgow and Siddharth Banka",
year = "2016",
month = feb,
day = "4",
doi = "10.1016/j.ajhg.2015.12.014",
language = "English",
volume = "98",
pages = "363--372",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

RIS

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 -