June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Allelic Heterogeneity Contributes to Variability in Ocular Dysgenesis, Myopathy, and Brain Malformations Caused by Col4a1 and Col4a2 Mutations
Author Affiliations & Notes
  • Debbie Kuo
    Ophthalmology, University of California, San Francisco, San Francisco, CA
  • Cassandre Labelle-Dumais
    Ophthalmology, University of California, San Francisco, San Francisco, CA
  • Mao Mao
    Ophthalmology, University of California, San Francisco, San Francisco, CA
  • Marion Jeanne
    Ophthalmology, University of California, San Francisco, San Francisco, CA
  • William Kauffman
    Ophthalmology, University of California, San Francisco, San Francisco, CA
  • Jennifer Allen
    Ophthalmology, University of California, San Francisco, San Francisco, CA
  • Jack Favor
    Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
  • Douglas Gould
    Ophthalmology, University of California, San Francisco, San Francisco, CA
    Anatomy and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA
  • Footnotes
    Commercial Relationships Debbie Kuo, None; Cassandre Labelle-Dumais, None; Mao Mao, None; Marion Jeanne, None; William Kauffman, None; Jennifer Allen, None; Jack Favor, None; Douglas Gould, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1347. doi:
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      Debbie Kuo, Cassandre Labelle-Dumais, Mao Mao, Marion Jeanne, William Kauffman, Jennifer Allen, Jack Favor, Douglas Gould; Allelic Heterogeneity Contributes to Variability in Ocular Dysgenesis, Myopathy, and Brain Malformations Caused by Col4a1 and Col4a2 Mutations. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1347.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Collagen type IV alpha 1, COL4A1, and its binding partner COL4A2 are present in nearly all basement membranes. COL4A1 and COL4A2 mutations are pleiotropic and associated with a broad spectrum of disorders including ocular dysgenesis and glaucoma. Recently we reported COL4A1 mutations in two patients with Muscle-Eye-Brain disease (MEB) and Walker-Warburg Syndrome (WWS) and demonstrated that Col4a1 mutant mice have ocular dysgenesis, myopathy and brain malformations modeling MEB/WWS. We showed that mutations in COL4A1 can affect the biosynthesis of COL4A1/COL4A2 heterotrimers, typically resulting in intracellular retention and impaired secretion of mutant protein. In this study, we investigate the contribution of allelic differences to the phenotypic variability associated with Col4a1 and Col4a2 mutations using an allelic series of mice.

Methods: We crossed eight distinct Col4a1 mutations and one Col4a2 mutation to C57BL/6J mice to generate an allelic series on a uniform genetic background. Clinical examination of the anterior segment and histological analyses of optic nerve, muscle and brain sections were performed to characterize ocular dysgenesis, myopathy and brain malformations. The effects of mutations on COL4A1/COL4A2 heterotrimer biosynthesis were evaluated using immunofluorescent labeling and Western blot analyses on primary mouse embryonic fibroblasts derived from mutant mouse lines.

Results: We identified allele-specific effects on the expression and severity of ocular dysgenesis, myopathy and brain malformations. We also found allelic differences in the levels of intracellular and extracellular COL4A1 and COL4A2. While most mutations demonstrated increased intracellular and decreased extracellular levels of COL4A1 and COL4A2, one mutation showed no significant difference in intracellular or extracellular levels of COL4A1 and COL4A2 compared to controls and one mutation showed both decreased intracellular and extracellular levels of COL4A1 and COL4A2.

Conclusions: Col4a1 and Col4a2 mutations can have distinct molecular consequences and lead to heterogeneous ocular, cerebral and myopathic phenotypes of variable severity. Allelic differences may reflect mechanistic heterogeneity and could provide valuable insight toward developing prognostic tools and targeted therapeutics for patients with COL4A1 and COL4A2 mutations.

Keywords: 539 genetics • 519 extracellular matrix  
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