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.
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Kasher
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Schertz
authors.affiliation: Child Health Directorate, Blackpool Teaching Hospitals, Blackpool FY3 8NR, UK; Faculty of Health and Medicine, University of Lancaster, Lancaster LA1 4YW, UK.
authors.forename: Megan
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Child Health Directorate, Blackpool Teaching Hospitals, Blackpool FY3 8NR, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Fondazione I.R.C.C.S. Istituto Neurologico "C. Besta," Milan 20133, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Annunziata
authors.affiliation: Sección de Genética Médica, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Cátedra de Genética, UCAM, 30120 Murcia, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Ballesta-Martinez
authors.affiliation: Department of Paediatrics, University of Montreal, Montréal, QC H3T 1J4, Canada.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.affiliation: Centre for Paediatrics & Child Health, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Clayton
authors.affiliation: Summa Health System, Akron, OH 44304, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Eaton
authors.affiliation: Fondazione I.R.C.C.S. Istituto Neurologico "C. Besta," Milan 20133, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Granata
authors.affiliation: Sección de Genética Médica, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Cátedra de Genética, UCAM, 30120 Murcia, Spain.
authors.forename: Encarna
authors.initials: E
authors.lastname: Guillén-Navarro
authors.affiliation: Quantitative Genomic Medicine Laboratories (qGenomics), 08950 Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernando
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Laverriere
authors.affiliation: Medical Genetics, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
authors.forename: Agne
authors.initials: A
authors.lastname: Liedén
authors.affiliation: Quantitative Genomic Medicine Laboratories (qGenomics), 08950 Barcelona, Spain.
authors.forename: Olaya
authors.initials: O
authors.lastname: Villa-Marcos
authors.affiliation: Medical Genetics, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
authors.forename: Meriel
authors.initials: M
authors.lastname: McEntagart
authors.affiliation: Department of Clinical Genetics, Karolinska University Hospital, Stockholm 171 76, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 171 76, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
authors.affiliation: Fondazione I.R.C.C.S. Istituto Neurologico "C. Besta," Milan 20133, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pantaleoni
authors.affiliation: Cytogénétique Médicale, CHU-Estaing, 63003 Clermont-Ferrand, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Pebrel-Richard
authors.affiliation: Génétique Médicale, Hôpital Estaing, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sarret
authors.affiliation: Fondazione I.R.C.C.S. Istituto Neurologico "C. Besta," Milan 20133, Italy.
authors.forename: Francesca L
authors.initials: FL
authors.lastname: Sciacca
authors.affiliation: 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.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Wright
authors.affiliation: 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.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Glasgow
authors.affiliation: 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.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Banka
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015992:Body Mass Index; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D010121:Oxytocin / Q000378:metabolism; D050809:POU Domain Factors / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D055815:Young Adult; D015027:Zebrafish
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D010121:Oxytocin; D050809:POU Domain Factors; D012097:Repressor Proteins; C491094:SIM1 protein, human; C085076:transcription factor Brn-2
keywords: 6q16; POU3F2 (also called BRN2 or N-OCT3 or OCT7); SIM1; intellectual disability; obesity; oxytocin
references.citation: Hum Mol Genet. 2000 Jan 1;9(1):101-8
references.pmid: 10587584
references.citation: Mech Dev. 2000 Feb;90(2):253-61
references.pmid: 10640708
references.citation: Nature. 2000 Apr 6;404(6778):632-4
references.pmid: 10766249
references.citation: Nature. 2001 Oct 4;413(6855):519-23
references.pmid: 11586359
references.citation: Science. 2002 Feb 22;295(5559):1528-32
references.pmid: 11859196
references.citation: Nat Genet. 2002 Jun;31(2):135-40
references.pmid: 12006978
references.citation: Genes Dev. 2002 Jul 15;16(14):1760-5
references.pmid: 12130536
references.citation: Ment Retard Dev Disabil Res Rev. 2002;8(3):117-34
references.pmid: 12216056
references.citation: Gene Expr Patterns. 2003 Mar;3(1):105-8
references.pmid: 12609611
references.citation: Lancet. 2003 Oct 25;362(9393):1366-73
references.pmid: 14585638
references.citation: PLoS Genet. 2005 Dec;1(6):e49
references.pmid: 16444292
references.citation: Nat Rev Genet. 2006 Apr;7(4):277-82
references.pmid: 16534515
references.citation: Dev Dyn. 2006 Aug;235(8):2071-82
references.pmid: 16691572
references.citation: Dev Cell. 2006 Dec;11(6):831-44
references.pmid: 17141158
references.citation: Dev Genes Evol. 2007 Feb;217(2):149-58
references.pmid: 17180684
references.citation: Dev Dyn. 2008 Apr;237(4):995-1005
references.pmid: 18330923
references.citation: Mol Endocrinol. 2008 Jul;22(7):1723-34
references.pmid: 18451093
references.citation: N Engl J Med. 2008 Aug 28;359(9):918-27
references.pmid: 18753648
references.citation: Eur J Neurosci. 2009 Dec;30(12):2239-49
references.pmid: 20092567
references.citation: PLoS Genet. 2010 Oct 14;6(10):e1001154
references.pmid: 20976243
references.citation: J Clin Invest. 2011 Jun;121(6):2080-6
references.pmid: 21633175
references.citation: Nat Genet. 2011 Aug 14;43(9):838-46
references.pmid: 21841781
references.citation: Nature. 2011 Oct 26;478(7370):483-9
references.pmid: 22031440
references.citation: Neurogenetics. 2012 Feb;13(1):31-47
references.pmid: 22218741
references.citation: Cereb Cortex. 2013 Nov;23(11):2632-43
references.pmid: 22892427
references.citation: Mol Biol Evol. 2013 Apr;30(4):844-52
references.pmid: 23197593
references.citation: J Clin Invest. 2013 Jul;123(7):3037-41
references.pmid: 23778136
references.citation: J Clin Invest. 2013 Jul;123(7):3042-50
references.pmid: 23778139
references.citation: Am J Hum Genet. 2013 Sep 5;93(3):482-95
references.pmid: 23993194
references.citation: Annu Rev Psychol. 2014;65:17-39
references.pmid: 24050183
references.citation: Ann Rheum Dis. 2015 Jun;74(6):1249-56
references.pmid: 24442880
references.citation: Nat Neurosci. 2014 Mar;17(3):391-9
references.pmid: 24464043
references.citation: Nat Commun. 2014 Mar 11;5:3339
references.pmid: 24618891
references.citation: Nat Genet. 2014 Oct;46(10):1063-71
references.pmid: 25217958
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D682-9
references.pmid: 25378326
references.citation: Nature. 2015 Mar 12;519(7542):223-8
references.pmid: 25533962
references.citation: Cell Rep. 2015 Nov 10;13(6):1073-1080
references.pmid: 26526993
references.citation: N Engl J Med. 1981 Feb 5;304(6):325-9
references.pmid: 7442771
references.citation: Genes Dev. 1995 Dec 15;9(24):3109-21
references.pmid: 8543155
references.citation: Genes Dev. 1995 Dec 15;9(24):3122-35
references.pmid: 8543156
references.citation: Dev Dyn. 1995 Jul;203(3):253-310
references.pmid: 8589427
references.citation: Genes Dev. 1998 Oct 15;12(20):3264-75
references.pmid: 9784500