When half is not enough: gene expression and dosage in the 22q11 deletion syndrome.
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.
Meechan
D W
DW
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.
Maynard
T M
TM
Gopalakrishna
D
D
Wu
Y
Y
LaMantia
A S
AS
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
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14433-8
14614146
Curr Biol. 2002 May 14;12(10):R366-71
12015140
Am J Hum Genet. 2002 Dec;71(6):1296-302
12402217
Mamm Genome. 1997 May;8(5):371-5
9107688
Int J Dev Neurosci. 2002 Jun-Aug;20(3-5):407-19
12175881
Mol Cell Neurosci. 2006 Dec;33(4):412-28
17097888
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3717-22
11891283
Am J Hum Genet. 2005 Mar;76(3):409-20
15662599
Behav Genet. 2006 May;36(3):346-54
16596471
Int Rev Neurobiol. 2004;59:273-96
15006492
Schizophr Res. 2006 Oct;87(1-3):21-7
16860541
J Neurosci. 2005 Jul 13;25(28):6533-8
16014714
J Med Genet. 2004 Apr;41(4):e40
15060116
Eur J Hum Genet. 2003 Apr;11(4):349-51
12700609
Neurogenetics. 2006 Nov;7(4):247-57
16900388
Neurosci Lett. 2005 Feb 1;374(1):21-4
15631889
Pflugers Arch. 2004 Feb;447(5):689-709
14598172
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6917-22
11381111
Cell. 2001 Feb 23;104(4):619-29
11239417
Am J Hum Genet. 1999 Aug;65(2):562-6
10417299
Am J Hum Genet. 1990 May;46(5):888-95
2339689
Bioessays. 1998 Jan;20(1):9-19
9504043
Biol Psychiatry. 1999 Jul 1;46(1):19-30
10394471
Development. 2002 Oct;129(19):4605-11
12223416
Hum Mol Genet. 1997 Feb;6(2):247-58
9063745
Nat Genet. 2004 Jul;36(7):725-31
15184899
Am J Med Genet. 1995 Jul 3;57(3):514-22
7677167
Dev Dyn. 2005 Jan;232(1):11-20
15580613
Trends Neurosci. 2001 Aug;24(8):479-86
11476888
Am J Dis Child. 1993 Nov;147(11):1212-6
8237917
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9991-6
9707588
Lancet. 2003 Oct 25;362(9393):1366-73
14585638
Am J Hum Genet. 1997 Sep;61(3):620-9
9326327
Genomics. 1990 Jul;7(3):299-306
2365351
Development. 1998 Aug;125(16):3111-21
9671584
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14608-13
9405660
Hum Genet. 1999 Oct;105(4):320-6
10543399
Hum Genet. 1997 Nov;101(1):6-12
9385360
Science. 1991 Oct 11;254(5029):282-5
1925583
Hum Genet. 2005 May;116(6):486-96
15778864
Am J Med Genet. 1996 Dec 18;66(3):250-6
8985481
Hum Mol Genet. 2005 Jan 15;14(2):241-53
15563509
Nature. 1999 Sep 23;401(6751):379-83
10517636
Dev Biol. 1998 Jun 15;198(2):277-85
9659933
J Cell Sci. 2003 Dec 15;116(Pt 24):4947-55
14625388
Mech Dev. 2000 Aug;96(1):121-4
10940632
Cereb Cortex. 2006 Jul;16 Suppl 1:i3-17
16766705
Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10300-10304
16801545
Ann Genet. 2004 Jul-Sep;47(3):235-40
15337468
Biol Psychiatry. 1999 Oct 1;46(7):882-91
10509171
Nature. 1999 Dec 2;402(6761):489-95
10591208
J Biol Chem. 1995 Jul 21;270(29):17442-56
7615550
Genome Res. 1997 Jan;7(1):17-26
9037598
Ann Genet. 1995;38(2):59-76
7486827
Am J Psychiatry. 2005 Sep;162(9):1736-8
16135635
Mol Cell Biol. 2002 Apr;22(7):2318-28
11884616
Rev Epidemiol Sante Publique. 2005 Nov;53 Spec No 2:2S87-95
16471148
Clin Genet. 2003 Apr;63(4):308-13
12702165
Science. 1999 Feb 19;283(5405):1158-61
10024240
Mutat Res. 1999 Aug;406(2-4):63-9
10479723
Pediatr Res. 2003 Apr;53(4):546-53
12612215
Pediatr Res. 2004 Sep;56(3):440-8
15333760
Genomics. 1998 Oct 15;53(2):146-54
9790763
Mech Dev. 2002 Feb;111(1-2):177-80
11804793
Nat Neurosci. 2005 Nov;8(11):1586-94
16234811
Genomics. 2000 Feb 1;63(3):374-83
10704284
Nat Genet. 1999 Apr;21(4):434-9
10192398
Schizophr Bull. 1983;9(4):571-82
6658393
Hum Mol Genet. 1999 Nov;8(12):2229-37
10545603
Genomics. 1991 May;10(1):201-6
2045103
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12309-14
8901577
Nature. 2001 Mar 1;410(6824):97-101
11242049
Mol Cell Biol. 2001 Mar;21(5):1854-65
11238922
Nat Genet. 2001 Mar;27(3):286-91
11242110
Mol Cell Biol. 2002 Jan;22(1):378-87
11739749
J Med Genet. 2001 Dec;38(12):E45
11748311
Development. 2003 Aug;130(15):3567-78
12810603
Hum Mol Genet. 2002 Sep 15;11(19):2243-9
12217952
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7729-34
16684884
Circ Res. 1999 Feb 5;84(2):127-35
9933243
Biol Psychiatry. 2005 Jul 1;58(1):78-80
15992527
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1763-8
12563036
Dev Biol. 2001 Jul 1;235(1):62-73
11412027
Development. 2006 Apr;133(7):1323-33
16510505
Am J Hum Genet. 1999 Jul;65(1):247-9
10364538
J Cell Sci. 2003 Aug 15;116(Pt 16):3399-411
12840069
Annu Rev Genomics Hum Genet. 2000;1:461-84
11701637
Science. 1994 May 6;264(5160):835-9
7513443
Am J Med Genet B Neuropsychiatr Genet. 2004 Aug 15;129B(1):13-5
15274030
Genet Med. 2001 Jan-Feb;3(1):6-13
11339380
Genomics. 1997 Aug 1;43(3):267-77
9268629
Am J Hum Genet. 2002 May;70(5):1077-88
11925570
Dev Biol. 2004 Mar 1;267(1):190-202
14975726
Biol Psychiatry. 1999 Jul 1;46(1):31-9
10394472
Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15018-23
16217027