title: Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.
abstract: Angelman syndrome (AS) is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG) abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%), paternal uniparental disomy (UPD) of chromosome 15 (5%), imprinting mutations (rare), and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%). Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+) were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+), but not paternal (m+/p-), deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV) recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal communication behaviors in human AS patients. Thus, mutant mice with a maternal deletion from Ube3a to Gabrb3 provide an AS mouse model that is molecularly more similar to the contiguous gene deletion form of AS in humans than mice with Ube3a mutation alone. These mice will be valuable for future comparative studies to mice with maternal deficiency of Ube3a alone.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. yong-hui.jiang@duke.edu
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.forename: Yanzhen
authors.initials: Y
authors.lastname: Pan
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Luis
authors.initials: L
authors.lastname: Landa
authors.forename: Jong
authors.initials: J
authors.lastname: Yoo
authors.forename: Corinne
authors.initials: C
authors.lastname: Spencer
authors.forename: Isabel
authors.initials: I
authors.lastname: Lorenzo
authors.forename: Murray
authors.initials: M
authors.lastname: Brilliant
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Noebels
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics; D017204:Angelman Syndrome / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology; D002872:Chromosome Deletion; D003624:Darkness; D004195:Disease Models, Animal; D005106:Exploratory Behavior; D005260:Female; D005786:Gene Expression Regulation; D006720:Homozygote; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D008568:Memory; D051379:Mice; D009035:Mothers; D009043:Motor Activity / Q000235:genetics; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics; D012640:Seizures / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics; D014465:Ultrasonics; D014828:Vocalization, Animal
chemical_list: C546273:GABRB3 protein, human; C546270:Gabrb3 protein, mouse; D026901:Membrane Transport Proteins; D011963:Receptors, GABA-A; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; C478764:ATP10a protein, mouse
references.citation: Neurogenetics. 2010 May;11(2):145-51
references.pmid: 19894069
references.citation: J Nutr Biochem. 2006 Dec;17(12):811-20
references.pmid: 16517145
references.citation: Genomics. 2003 Jun;81(6):644-7
references.pmid: 12782135
references.citation: Hum Mol Genet. 2008 Jul 15;17(14):2181-9
references.pmid: 18413322
references.citation: Hum Mol Genet. 2007 Mar 15;16(6):691-703
references.pmid: 17339270
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2050-4
references.pmid: 8095339
references.citation: J Hum Genet. 2003;48(4):194-8
references.pmid: 12730723
references.citation: Curr Biol. 2008 Mar 11;18(5):354-62
references.pmid: 18328704
references.citation: Nat Neurosci. 2007 Mar;10(3):280-2
references.pmid: 17259980
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3117-22
references.pmid: 18287060
references.citation: Neuron. 2002 Jul 18;35(2):243-54
references.pmid: 12160743
references.citation: J Med Genet. 2003 Feb;40(2):87-95
references.pmid: 12566516
references.citation: Nat Rev Genet. 2001 Oct;2(10):780-90
references.pmid: 11584294
references.citation: Cell. 2009 Jun 26;137(7):1235-46
references.pmid: 19563756
references.citation: J Clin Invest. 2006 Nov;116(11):3035-41
references.pmid: 17024248
references.citation: Behav Brain Res. 2001 Nov 1;125(1-2):49-56
references.pmid: 11682093
references.citation: Annu Rev Genomics Hum Genet. 2006;7:247-76
references.pmid: 16824018
references.citation: Clin Genet. 2004 Dec;66(6):530-6
references.pmid: 15521981
references.citation: Ann Neurol. 1998 Apr;43(4):485-93
references.pmid: 9546330
references.citation: Neuron. 1998 Oct;21(4):799-811
references.pmid: 9808466
references.citation: J Med Genet. 2001 Dec;38(12):834-45
references.pmid: 11748306
references.citation: BMC Genomics. 2008 Jan 28;9:50
references.pmid: 18226259
references.citation: Neurobiol Dis. 2002 Mar;9(2):149-59
references.pmid: 11895368
references.citation: Curr Opin Genet Dev. 2007 Jun;17(3):182-92
references.pmid: 17467974
references.citation: Hum Mol Genet. 1997 Nov;6(12):2127-33
references.pmid: 9328477
references.citation: Nat Genet. 1997 Jan;15(1):74-7
references.pmid: 8988172
references.citation: Nat Genet. 2007 Jul;39(7 Suppl):S43-7
references.pmid: 17597781
references.citation: J Nutr. 2004 Apr;134(4):799-805
references.pmid: 15051828
references.citation: Brain Res Dev Brain Res. 2005 Jun 30;157(2):150-61
references.pmid: 15878204
references.citation: Psychiatr Genet. 2005 Dec;15(4):243-54
references.pmid: 16314754
references.citation: Physiol Behav. 2006 Jan 30;87(1):95-102
references.pmid: 16197969
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9643-8
references.pmid: 15983371
references.citation: Mol Cell Biol. 2000 Jan;20(2):648-55
references.pmid: 10611243
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11074-9
references.pmid: 20534473
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1710-5
references.pmid: 18227507
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4143-8
references.pmid: 9108119
references.citation: Nat Genet. 1997 Sep;17(1):75-8
references.pmid: 9288101
references.citation: J Hum Genet. 2003;48(9):492-493
references.pmid: 12955587
references.citation: Nat Genet. 1997 Jan;15(1):70-3
references.pmid: 8988171
references.citation: Am J Ment Retard. 2006 Sep;111(5):311-21
references.pmid: 16968140
references.citation: Behav Genet. 2002 Jul;32(4):267-73
references.pmid: 12211626
references.citation: Curr Protoc Neurosci. 2002 Feb;Chapter 8:Unit 8.14
references.pmid: 18428567
references.citation: N Engl J Med. 2008 Feb 14;358(7):667-75
references.pmid: 18184952
references.citation: Neurosci Biobehav Rev. 2009 Apr;33(4):508-15
references.pmid: 18771687
references.citation: Am J Med Genet C Semin Med Genet. 2006 Feb 15;142C(1):40-51
references.pmid: 16419099
references.citation: Hum Mol Genet. 1999 Aug;8(8):1357-64
references.pmid: 10400982
references.citation: Genesis. 2003 Jul;36(3):142-8
references.pmid: 12872245
references.citation: Neuron. 2006 Oct 5;52(1):103-21
references.pmid: 17015230
references.citation: Semin Pediatr Neurol. 2007 Sep;14(3):108-17
references.pmid: 17980307
references.citation: Hum Genet. 2008 Oct;124(3):235-42
references.pmid: 18726118
references.citation: Am J Hum Genet. 2001 Jun;68(6):1501-5
references.pmid: 11353404
references.citation: Nat Genet. 2003 May;34(1):27-9
references.pmid: 12669065
references.citation: Epileptic Disord. 2005 Mar;7(1):19-25
references.pmid: 15741136
references.citation: Mol Cell Biol. 2003 May;23(10):3646-55
references.pmid: 12724422
references.citation: Am J Hum Genet. 2003 Oct;73(4):898-925
references.pmid: 14508708
references.citation: Science. 2004 Jun 25;304(5679):1983-6
references.pmid: 15218152
references.citation: Nat Genet. 2001 May;28(1):19-20
references.pmid: 11326269
references.citation: Neurologist. 2007 Sep;13(5):305-12
references.pmid: 17848870
references.citation: Nature. 1995 Dec 14;378(6558):720-4
references.pmid: 7501018
references.citation: Annu Rev Genomics Hum Genet. 2004;5:379-405
references.pmid: 15485354
references.citation: Am J Hum Genet. 1999 Jul;65(1):1-6
references.pmid: 10364509
references.citation: J Child Psychol Psychiatry. 2007 Jun;48(6):571-9
references.pmid: 17537073
references.citation: PLoS One. 2008 Aug 27;3(8):e3067
references.pmid: 18728777
references.citation: Hum Mol Genet. 2007 Aug 1;16(15):1802-13
references.pmid: 17517686
references.citation: Hum Mol Genet. 2008 Jan 1;17(1):111-8
references.pmid: 17940072
references.citation: Behav Genet. 2005 Jan;35(1):31-52
references.pmid: 15674531
references.citation: Neuron. 2008 Mar 27;57(6):809-18
references.pmid: 18367082
references.citation: Nature. 2001 Oct 4;413(6855):519-23
references.pmid: 11586359
references.citation: Neuroreport. 2006 Apr 3;17(5):541-4
references.pmid: 16543822
references.citation: Am J Ment Retard. 2002 May;107(3):194-200
references.pmid: 11966332