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Am J Hum Genet. 2016 Feb 4;98(2):363-72. doi: 10.1016/j.ajhg.2015.12.014. Epub 2016 Jan 28.

Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

Author information

1
Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, UK.
2
Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
3
Child Health Directorate, Blackpool Teaching Hospitals, Blackpool FY3 8NR, UK; Faculty of Health and Medicine, University of Lancaster, Lancaster LA1 4YW, UK.
4
Child Health Directorate, Blackpool Teaching Hospitals, Blackpool FY3 8NR, UK.
5
Fondazione I.R.C.C.S. Istituto Neurologico "C. Besta," Milan 20133, Italy.
6
Sección de Genética Médica, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Cátedra de Genética, UCAM, 30120 Murcia, Spain.
7
Department of Paediatrics, University of Montreal, Montréal, QC H3T 1J4, Canada.
8
Centre for Paediatrics & Child Health, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
9
Summa Health System, Akron, OH 44304, USA.
10
Quantitative Genomic Medicine Laboratories (qGenomics), 08950 Barcelona, Spain.
11
Medical Genetics, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
12
Department of Clinical Genetics, Karolinska University Hospital, Stockholm 171 76, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 76, Sweden.
13
Cytogénétique Médicale, CHU-Estaing, 63003 Clermont-Ferrand, France.
14
Génétique Médicale, Hôpital Estaing, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France.
15
Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK.
16
Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK.
17
Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK. Electronic address: siddharth.banka@manchester.ac.uk.

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:

6q16; POU3F2 (also called BRN2 or N-OCT3 or OCT7); SIM1; intellectual disability; obesity; oxytocin

PMID:
26833329
PMCID:
PMC4746363
DOI:
10.1016/j.ajhg.2015.12.014
[Indexed for MEDLINE]
Free PMC Article

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