Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice

Author： McLaughlin Precious J. Bakall Benjamin Choi Jiwon Liu Zhonglin Sasaki Takako Davis Elaine C. Marmorstein Alan D. Marmorstein Lihua Y.

Publisher： Oxford University Press

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.16, Iss.24, 2007-12, pp. : 3059-3070

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Abstract

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.