Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35).
Precisely regulated temporal and spatial patterns of gene expression are essential for proper human development. Cis-acting regulatory elements, some located at large distances from their corresponding genes, play a critical role in transcriptional control of key developmental genes and disruption of these regulatory elements can lead to disease. We report a three generation family with five affected members, all of whom have hearing loss, craniofacial defects, and a paracentric inversion of the long arm of chromosome 7, inv(7)(q21.3q35). High resolution mapping of the inversion showed that the 7q21.3 breakpoint is located 65 and 80 kb centromeric of DLX6 and DLX5, respectively. Further analysis revealed a 5,115 bp deletion at the 7q21.3 breakpoint. While the breakpoint does not disrupt either DLX5 or DLX6, the syndrome present in the family is similar to that observed in Dlx5 knockout mice and includes a subset of the features observed in individuals with DLX5 and DLX6 deletions, implicating dysregulation of DLX5 and DLX6 in the family's phenotype. Bioinformatic analysis indicates that the 5,115 bp deletion at the 7q21.3 breakpoint could contain regulatory elements necessary for DLX5 and DLX6 expression. Using a transgenic mouse reporter assay, we show that the deleted sequence can drive expression in the inner ear and developing bones of E12.5 embryos. Consequently, the observed familial syndrome is likely caused by dysregulation of DLX5 and/or DLX6 in specific tissues due to deletion of an enhancer and possibly separation from other regulatory elements by the chromosomal inversion.
Brown
Kerry K
KK
Department of Genetics, Harvard Medical School, Boston, MA, USA. kerry_kocher@student.hms.harvard.edu
Reiss
Jacob A
JA
Crow
Kate
K
Ferguson
Heather L
HL
Kelly
Chantal
C
Fritzsch
Bernd
B
Morton
Cynthia C
CC
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D007446:Chromosome Inversion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000473:pathology; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005192:Family Health; D005260:Female; D018014:Gene Transfer Techniques; D034381:Hearing Loss / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008875:Middle Aged; D010375:Pedigree; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*
C100596:DLX5 protein, human; C491014:DLX6 protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors
Development. 1999 Sep;126(17):3831-46
10433912
Mol Psychiatry. 2008 Mar;13(3):261-6
17646849
Am J Hum Genet. 2008 Jan;82(1):160-4
18179894
Am J Hum Genet. 2007 Sep;81(3):492-506
17701895
Nucleic Acids Res. 1995 Dec 11;23(23):4878-84
8532532
N Engl J Med. 2006 Mar 30;354(13):1370-7
16571880
Eur J Med Genet. 2008 Nov-Dec;51(6):631-8
18675947
Hum Mol Genet. 2003 Jul 15;12(14):1725-35
12837695
Nucleic Acids Res. 1995 Mar 25;23(6):1087-8
7731798
Neuron. 1997 Jul;19(1):27-37
9247261
Int J Pediatr Otorhinolaryngol. 2003 Oct;67(10):1127-32
14550969
Development. 2006 Feb;133(4):761-72
16407397
Am J Hum Genet. 2008 Jan;82(1):165-73
18179895
Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2250-4
7907794
Dev Biol. 2002 Aug 1;248(1):157-69
12142028
Nat Genet. 2005 Jan;37(1):31-40
15608638
J Med Genet. 2001 Jun;38(6):405-9
11424924
Dev Biol. 2006 Mar 15;291(2):382-97
16458883
J Cell Biol. 2003 Sep 15;162(6):1149-60
12963709
Int J Dev Biol. 2000;44(6):619-26
11061425
Genomics. 2003 Jul;82(1):1-9
12809671
J Neurosci. 2000 Jan 15;20(2):709-21
10632600
Nature. 2006 Nov 23;444(7118):499-502
17086198
Genome Res. 2003 Jan;13(1):97-102
12529311
J Med Genet. 2004 May;41(5):e54
15121782
Eur J Hum Genet. 2007 Jun;15(6):711-3
17392702
Mol Cell Biol. 1993 Sep;13(9):5604-12
8355703
Genesis. 2002 Jun;33(2):97-101
12112878
J Cell Mol Med. 2008 Aug;12(4):1188-91
18537997
Am J Med Genet A. 2007 Jan 1;143A(1):27-32
17152067
Dev Cell. 2007 Apr;12(4):645-52
17420000
Genome Res. 2003 Jan;13(1):73-80
12529308
Genes Dev. 2002 May 1;16(9):1089-101
12000792
Development. 1999 Sep;126(17):3795-809
10433909
Nat Genet. 1996 Nov;14(3):357-60
8896572
Nat Genet. 1996 Nov;14(3):353-6
8896571
Hum Mol Genet. 1994 Aug;3(8):1345-54
7987313
Am J Hum Genet. 2008 Jan;82(1):150-9
18179893
Hum Genet. 1997 Aug;100(2):172-81
9254845
Am J Hum Genet. 2005 Jan;76(1):8-32
15549674
Dev Biol. 2006 Nov 15;299(2):563-81
17014839
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7548-53
12032320
J Mol Biol. 1990 Oct 5;215(3):403-10
2231712
Neuron. 1999 Dec;24(4):1037-47
10624965