Journal article
Rare variants in BMP2 and BMP4 found in otosclerosis patients reduce Smad signaling
Otology & neurotology, Vol.35(3), pp.395-400
03/2014
DOI: 10.1097/MAO.0000000000000244
PMCID: PMC3945298
PMID: 24492129
Abstract
Hypothesis
Genetic variation in BMP2 and BMP4 found in otosclerosis patients result in altered Smad signaling.
Background
Otosclerosis is a common form of adult-onset conductive hearing loss resulting from abnormal bone remodeling of the bony labyrinth that surrounds the inner ear. Both genetic and environmental factors are implicated in the disease, yet very little is known about its pathogenesis. The evidence for a genetic component has been established through family-based linkage and population-based association studies. Previously, members of the TGF-β superfamily of genes have been associated with otosclerosis.
Methods
Sequencing of BMP2 and BMP4 coding regions was performed to identify common and rare variation in German otosclerosis patients compared with controls. Functional analyses of rare variation in the patient cohort were conducted by exposing an osteosarcoma cell line to conditioned media containing either wild type or variant forms of BMP2 or BMP4 and analyzing Smad1/5/8 phosphorylation.
Results
Although no significant association with common variation in these 2 genes was detected, there were 8 singleton variants identified in the German population. Of the 4 coding variants found solely in otosclerosis patients, two—BMP4N150K and BMP2K357-R396del—were found to decrease Smad1/5/8 signaling.
Conclusion
Rare variants in BMP2 and BMP4 are not a major genetic component in the otosclerosis population. However, those with functional affect showed decreased Smad signaling. Further analysis of Smad signaling molecules should be performed to determine if these pathways in combination are a major contributor to otosclerosis, which could lead to additional treatment options for otosclerosis patients.
Details
- Title: Subtitle
- Rare variants in BMP2 and BMP4 found in otosclerosis patients reduce Smad signaling
- Creators
- Megan Ealy - Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USANicole C Meyer - Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USAJohnny Cruz Corchado - Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USAIsabelle Schrauwen - Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, BelgiumAndreas Bress - Department of Otorhinolaryngology, University of Tübingen, D-72074 Tübingen, GermanyMarkus Pfister - Department of Otorhinolaryngology, University of Tübingen, D-72074 Tübingen, GermanyGuy Van Camp - Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, BelgiumRichard JH Smith - Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Otology & neurotology, Vol.35(3), pp.395-400
- DOI
- 10.1097/MAO.0000000000000244
- PMID
- 24492129
- PMCID
- PMC3945298
- NLM abbreviation
- Otol Neurotol
- ISSN
- 1531-7129
- eISSN
- 1537-4505
- Language
- English
- Date published
- 03/2014
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biology; Otolaryngology; Internal Medicine
- Record Identifier
- 9984007159902771
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