Journal article
Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35)
Human genetics, Vol.127(1), pp.19-31
01/2010
DOI: 10.1007/s00439-009-0736-4
PMCID: PMC2847447
PMID: 19707792
Abstract
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.
Details
- Title: Subtitle
- Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35)
- Creators
- Kerry Brown - Department of Genetics Harvard Medical School Boston MA USAJacob Reiss - Department of Genetics Kaiser Permanente Northwest Portland OR USAKate Crow - Department of Genetics Kaiser Permanente Northwest Portland OR USAHeather Ferguson - Departments of Obstetrics, Gynecology, and Reproductive Biology and Pathology Brigham and Women’s Hospital and Harvard Medical School 77 Avenue Louis Pasteur, NRB 160 Boston MA 02115 USAChantal Kelly - Departments of Obstetrics, Gynecology, and Reproductive Biology and Pathology Brigham and Women’s Hospital and Harvard Medical School 77 Avenue Louis Pasteur, NRB 160 Boston MA 02115 USABernd Fritzsch - Department of Biology University of Iowa Iowa City IA USACynthia Morton - Departments of Obstetrics, Gynecology, and Reproductive Biology and Pathology Brigham and Women’s Hospital and Harvard Medical School 77 Avenue Louis Pasteur, NRB 160 Boston MA 02115 USA
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.127(1), pp.19-31
- DOI
- 10.1007/s00439-009-0736-4
- PMID
- 19707792
- PMCID
- PMC2847447
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Publisher
- Springer-Verlag; Berlin/Heidelberg
- Language
- English
- Date published
- 01/2010
- Academic Unit
- Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center
- Record Identifier
- 9984070429402771
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