title: When half is not enough: gene expression and dosage in the 22q11 deletion syndrome.
abstract: The 22q11 Deletion Syndrome (22q11DS, also known as DiGeorge or Velo-Cardio-Facial Syndrome) has a variable constellation of phenotypes including life-threatening cardiac malformations, craniofacial, limb, and digit anomalies, a high incidence of learning, language, and behavioral disorders, and increased vulnerability for psychiatric diseases, including schizophrenia. There is still little clear understanding of how heterozygous microdeletion of approximately 30-50 genes on chromosome 22 leads to this diverse spectrum of phenotypes, especially in the brain. Three possibilities exist: 1) 22q11DS may reflect haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a single gene within the deleted region; 2) 22q11DS may result from haploinsufficiency, homozygous loss of function, or heterozygous gain of function of a few genes in the deleted region acting at distinct phenotypically compromised sites; 3) 22q11DS may reflect combinatorial effects of reduced dosage of multiple genes acting in concert at all phenotypically compromised sites. Here, we consider evidence for each of these possibilities. Our review of the literature, as well as interpretation of work from our laboratory, favors the third possibility: 22q11DS reflects diminished expression of multiple 22q11 genes acting on common cellular processes during brain as well as heart, face, and limb development, and subsequently in the adolescent and adult brain.
authors: Department of Cell & Molecular Physiology, UNC Neuroscience Center, & Silvio M. Conte Center for Research in Mental Diseases, University of North Carolina-Chapel Hill, Chapel Hill, NC 27516-3005, USA.
authors: D W
authors: DW
authors: Meechan
authors: T M
authors: TM
authors: Maynard
authors: D
authors: D
authors: Gopalakrishna
authors: Y
authors: Y
authors: Wu
authors: A S
authors: AS
authors: LaMantia
mesh_terms: D000782:Aneuploidy; D000818:Animals; D004062:DiGeorge Syndrome / Q000235:genetics*; D018628:Gene Dosage / Q000502:physiology*; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010641:Phenotype
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14433-8
references: 14614146
references: Curr Biol. 2002 May 14;12(10):R366-71
references: 12015140
references: Am J Hum Genet. 2002 Dec;71(6):1296-302
references: 12402217
references: Mamm Genome. 1997 May;8(5):371-5
references: 9107688
references: Int J Dev Neurosci. 2002 Jun-Aug;20(3-5):407-19
references: 12175881
references: Mol Cell Neurosci. 2006 Dec;33(4):412-28
references: 17097888
references: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3717-22
references: 11891283
references: Am J Hum Genet. 2005 Mar;76(3):409-20
references: 15662599
references: Behav Genet. 2006 May;36(3):346-54
references: 16596471
references: Int Rev Neurobiol. 2004;59:273-96
references: 15006492
references: Schizophr Res. 2006 Oct;87(1-3):21-7
references: 16860541
references: J Neurosci. 2005 Jul 13;25(28):6533-8
references: 16014714
references: J Med Genet. 2004 Apr;41(4):e40
references: 15060116
references: Eur J Hum Genet. 2003 Apr;11(4):349-51
references: 12700609
references: Neurogenetics. 2006 Nov;7(4):247-57
references: 16900388
references: Neurosci Lett. 2005 Feb 1;374(1):21-4
references: 15631889
references: Pflugers Arch. 2004 Feb;447(5):689-709
references: 14598172
references: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22
references: 11381111
references: Cell. 2001 Feb 23;104(4):619-29
references: 11239417
references: Am J Hum Genet. 1999 Aug;65(2):562-6
references: 10417299
references: Am J Hum Genet. 1990 May;46(5):888-95
references: 2339689
references: Bioessays. 1998 Jan;20(1):9-19
references: 9504043
references: Biol Psychiatry. 1999 Jul 1;46(1):19-30
references: 10394471
references: Development. 2002 Oct;129(19):4605-11
references: 12223416
references: Hum Mol Genet. 1997 Feb;6(2):247-58
references: 9063745
references: Nat Genet. 2004 Jul;36(7):725-31
references: 15184899
references: Am J Med Genet. 1995 Jul 3;57(3):514-22
references: 7677167
references: Dev Dyn. 2005 Jan;232(1):11-20
references: 15580613
references: Trends Neurosci. 2001 Aug;24(8):479-86
references: 11476888
references: Am J Dis Child. 1993 Nov;147(11):1212-6
references: 8237917
references: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9991-6
references: 9707588
references: Lancet. 2003 Oct 25;362(9393):1366-73
references: 14585638
references: Am J Hum Genet. 1997 Sep;61(3):620-9
references: 9326327
references: Genomics. 1990 Jul;7(3):299-306
references: 2365351
references: Development. 1998 Aug;125(16):3111-21
references: 9671584
references: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14608-13
references: 9405660
references: Hum Genet. 1999 Oct;105(4):320-6
references: 10543399
references: Hum Genet. 1997 Nov;101(1):6-12
references: 9385360
references: Science. 1991 Oct 11;254(5029):282-5
references: 1925583
references: Hum Genet. 2005 May;116(6):486-96
references: 15778864
references: Am J Med Genet. 1996 Dec 18;66(3):250-6
references: 8985481
references: Hum Mol Genet. 2005 Jan 15;14(2):241-53
references: 15563509
references: Nature. 1999 Sep 23;401(6751):379-83
references: 10517636
references: Dev Biol. 1998 Jun 15;198(2):277-85
references: 9659933
references: J Cell Sci. 2003 Dec 15;116(Pt 24):4947-55
references: 14625388
references: Mech Dev. 2000 Aug;96(1):121-4
references: 10940632
references: Cereb Cortex. 2006 Jul;16 Suppl 1:i3-17
references: 16766705
references: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10300-10304
references: 16801545
references: Ann Genet. 2004 Jul-Sep;47(3):235-40
references: 15337468
references: Biol Psychiatry. 1999 Oct 1;46(7):882-91
references: 10509171
references: Nature. 1999 Dec 2;402(6761):489-95
references: 10591208
references: J Biol Chem. 1995 Jul 21;270(29):17442-56
references: 7615550
references: Genome Res. 1997 Jan;7(1):17-26
references: 9037598
references: Ann Genet. 1995;38(2):59-76
references: 7486827
references: Am J Psychiatry. 2005 Sep;162(9):1736-8
references: 16135635
references: Mol Cell Biol. 2002 Apr;22(7):2318-28
references: 11884616
references: Rev Epidemiol Sante Publique. 2005 Nov;53 Spec No 2:2S87-95
references: 16471148
references: Clin Genet. 2003 Apr;63(4):308-13
references: 12702165
references: Science. 1999 Feb 19;283(5405):1158-61
references: 10024240
references: Mutat Res. 1999 Aug;406(2-4):63-9
references: 10479723
references: Pediatr Res. 2003 Apr;53(4):546-53
references: 12612215
references: Pediatr Res. 2004 Sep;56(3):440-8
references: 15333760
references: Genomics. 1998 Oct 15;53(2):146-54
references: 9790763
references: Mech Dev. 2002 Feb;111(1-2):177-80
references: 11804793
references: Nat Neurosci. 2005 Nov;8(11):1586-94
references: 16234811
references: Genomics. 2000 Feb 1;63(3):374-83
references: 10704284
references: Nat Genet. 1999 Apr;21(4):434-9
references: 10192398
references: Schizophr Bull. 1983;9(4):571-82
references: 6658393
references: Hum Mol Genet. 1999 Nov;8(12):2229-37
references: 10545603
references: Genomics. 1991 May;10(1):201-6
references: 2045103
references: Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12309-14
references: 8901577
references: Nature. 2001 Mar 1;410(6824):97-101
references: 11242049
references: Mol Cell Biol. 2001 Mar;21(5):1854-65
references: 11238922
references: Nat Genet. 2001 Mar;27(3):286-91
references: 11242110
references: Mol Cell Biol. 2002 Jan;22(1):378-87
references: 11739749
references: J Med Genet. 2001 Dec;38(12):E45
references: 11748311
references: Development. 2003 Aug;130(15):3567-78
references: 12810603
references: Hum Mol Genet. 2002 Sep 15;11(19):2243-9
references: 12217952
references: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7729-34
references: 16684884
references: Circ Res. 1999 Feb 5;84(2):127-35
references: 9933243
references: Biol Psychiatry. 2005 Jul 1;58(1):78-80
references: 15992527
references: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1763-8
references: 12563036
references: Dev Biol. 2001 Jul 1;235(1):62-73
references: 11412027
references: Development. 2006 Apr;133(7):1323-33
references: 16510505
references: Am J Hum Genet. 1999 Jul;65(1):247-9
references: 10364538
references: J Cell Sci. 2003 Aug 15;116(Pt 16):3399-411
references: 12840069
references: Annu Rev Genomics Hum Genet. 2000;1:461-84
references: 11701637
references: Science. 1994 May 6;264(5160):835-9
references: 7513443
references: Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):13-5
references: 15274030
references: Genet Med. 2001 Jan-Feb;3(1):6-13
references: 11339380
references: Genomics. 1997 Aug 1;43(3):267-77
references: 9268629
references: Am J Hum Genet. 2002 May;70(5):1077-88
references: 11925570
references: Dev Biol. 2004 Mar 1;267(1):190-202
references: 14975726
references: Biol Psychiatry. 1999 Jul 1;46(1):31-9
references: 10394472
references: Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15018-23
references: 16217027