Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.
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.
Jiang
Yong-Hui
YH
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America. yong-hui.jiang@duke.edu
Pan
Yanzhen
Y
Zhu
Li
L
Landa
Luis
L
Yoo
Jong
J
Spencer
Corinne
C
Lorenzo
Isabel
I
Brilliant
Murray
M
Noebels
Jeffrey
J
Beaudet
Arthur L
AL
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
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
Neurogenetics. 2010 May;11(2):145-51
19894069
J Nutr Biochem. 2006 Dec;17(12):811-20
16517145
Genomics. 2003 Jun;81(6):644-7
12782135
Hum Mol Genet. 2008 Jul 15;17(14):2181-9
18413322
Hum Mol Genet. 2007 Mar 15;16(6):691-703
17339270
Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2050-4
8095339
J Hum Genet. 2003;48(4):194-8
12730723
Curr Biol. 2008 Mar 11;18(5):354-62
18328704
Nat Neurosci. 2007 Mar;10(3):280-2
17259980
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3117-22
18287060
Neuron. 2002 Jul 18;35(2):243-54
12160743
J Med Genet. 2003 Feb;40(2):87-95
12566516
Nat Rev Genet. 2001 Oct;2(10):780-90
11584294
Cell. 2009 Jun 26;137(7):1235-46
19563756
J Clin Invest. 2006 Nov;116(11):3035-41
17024248
Behav Brain Res. 2001 Nov 1;125(1-2):49-56
11682093
Annu Rev Genomics Hum Genet. 2006;7:247-76
16824018
Clin Genet. 2004 Dec;66(6):530-6
15521981
Ann Neurol. 1998 Apr;43(4):485-93
9546330
Neuron. 1998 Oct;21(4):799-811
9808466
J Med Genet. 2001 Dec;38(12):834-45
11748306
BMC Genomics. 2008 Jan 28;9:50
18226259
Neurobiol Dis. 2002 Mar;9(2):149-59
11895368
Curr Opin Genet Dev. 2007 Jun;17(3):182-92
17467974
Hum Mol Genet. 1997 Nov;6(12):2127-33
9328477
Nat Genet. 1997 Jan;15(1):74-7
8988172
Nat Genet. 2007 Jul;39(7 Suppl):S43-7
17597781
J Nutr. 2004 Apr;134(4):799-805
15051828
Brain Res Dev Brain Res. 2005 Jun 30;157(2):150-61
15878204
Psychiatr Genet. 2005 Dec;15(4):243-54
16314754
Physiol Behav. 2006 Jan 30;87(1):95-102
16197969
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9643-8
15983371
Mol Cell Biol. 2000 Jan;20(2):648-55
10611243
Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):11074-9
20534473
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1710-5
18227507
Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4143-8
9108119
Nat Genet. 1997 Sep;17(1):75-8
9288101
J Hum Genet. 2003;48(9):492-493
12955587
Nat Genet. 1997 Jan;15(1):70-3
8988171
Am J Ment Retard. 2006 Sep;111(5):311-21
16968140
Behav Genet. 2002 Jul;32(4):267-73
12211626
Curr Protoc Neurosci. 2002 Feb;Chapter 8:Unit 8.14
18428567
N Engl J Med. 2008 Feb 14;358(7):667-75
18184952
Neurosci Biobehav Rev. 2009 Apr;33(4):508-15
18771687
Am J Med Genet C Semin Med Genet. 2006 Feb 15;142C(1):40-51
16419099
Hum Mol Genet. 1999 Aug;8(8):1357-64
10400982
Genesis. 2003 Jul;36(3):142-8
12872245
Neuron. 2006 Oct 5;52(1):103-21
17015230
Semin Pediatr Neurol. 2007 Sep;14(3):108-17
17980307
Hum Genet. 2008 Oct;124(3):235-42
18726118
Am J Hum Genet. 2001 Jun;68(6):1501-5
11353404
Nat Genet. 2003 May;34(1):27-9
12669065
Epileptic Disord. 2005 Mar;7(1):19-25
15741136
Mol Cell Biol. 2003 May;23(10):3646-55
12724422
Am J Hum Genet. 2003 Oct;73(4):898-925
14508708
Science. 2004 Jun 25;304(5679):1983-6
15218152
Nat Genet. 2001 May;28(1):19-20
11326269
Neurologist. 2007 Sep;13(5):305-12
17848870
Nature. 1995 Dec 14;378(6558):720-4
7501018
Annu Rev Genomics Hum Genet. 2004;5:379-405
15485354
Am J Hum Genet. 1999 Jul;65(1):1-6
10364509
J Child Psychol Psychiatry. 2007 Jun;48(6):571-9
17537073
PLoS One. 2008 Aug 27;3(8):e3067
18728777
Hum Mol Genet. 2007 Aug 1;16(15):1802-13
17517686
Hum Mol Genet. 2008 Jan 1;17(1):111-8
17940072
Behav Genet. 2005 Jan;35(1):31-52
15674531
Neuron. 2008 Mar 27;57(6):809-18
18367082
Nature. 2001 Oct 4;413(6855):519-23
11586359
Neuroreport. 2006 Apr 3;17(5):541-4
16543822
Am J Ment Retard. 2002 May;107(3):194-200
11966332