Human Molecular Genetics Advance Access originally published online on September 13, 2007
Human Molecular Genetics 2007 16(24):3059-3070; doi:10.1093/hmg/ddm264
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Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice
1 Department of Ophthalmology and Vision Science, 2 Department of Radiology, 3 Optical Sciences Center, 4 Department of Physiology, University of Arizona, Tucson, AZ, USA, 5 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada and 6 Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR, USA
* To whom correspondence should be addressed at: Department of Ophthalmology and Vision Science, University of Arizona, 655 N Alvernon Way, Suite 108, Tucson, AZ 85711, USA. Tel: +1 5206260447; Fax: +1 5206260457; Email: lmarmorstein{at}eyes.arizona.edu
Received August 14, 2007; Accepted September 11, 2007
A mutation in the EFEMP1 gene causes Malattia Leventinese, an inherited macular degenerative disease with strong similarities to age-related macular degeneration. EFEMP1 encodes fibulin-3, an extracellular matrix protein of unknown function. To investigate its biological role, the murine Efemp1 gene was inactivated through targeted disruption. Efemp1–/– mice exhibited reduced reproductivity, and displayed an early onset of aging-associated phenotypes including reduced lifespan, decreased body mass, lordokyphosis, reduced hair growth, and generalized fat, muscle and organ atrophy. However, these mice appeared to have normal wound healing ability. Efemp1–/– mice on a C57BL/6 genetic background developed multiple large hernias including inguinal hernias, pelvic prolapse and protrusions of the xiphoid process. In contrast, Efemp1–/– mice on a BALB/c background rarely had any forms of hernias, indicating the presence of modifiers for fibulin-3's function in different mouse strains. Histological analysis revealed a marked reduction of elastic fibers in fascia, a thin layer of connective tissue maintaining and protecting structures throughout the body. No apparent macular degeneration associated defects were found in Efemp1–/– mice, suggesting that loss of fibulin-3 function is not the mechanism by which the mutation in EFEMP1 causes macular degeneration. These data demonstrate that fibulin-3 plays an important role in maintaining the integrity of fascia connective tissues and regulates aging.
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