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Bellingham J, Davidson AE, Aboshiha J, et al. Investigation of Aberrant Splicing Induced by AIPL1 Variations as a Cause of Leber Congenital Amaurosis. Invest Ophthalmol Vis Sci. 2015;56(13):7784-7793doi: 10.1167/iovs.15-18092.
Bellingham, J., Davidson, A. E., Aboshiha, J., Simonelli, F., Bainbridge, J. W., Michaelides, M., & van der Spuy, J. (2015). Investigation of Aberrant Splicing Induced by AIPL1 Variations as a Cause of Leber Congenital Amaurosis. Investigative ophthalmology & visual science, 56(13), 7784-7793. https://doi.org/10.1167/iovs.15-18092
Bellingham, James, et al. "Investigation of Aberrant Splicing Induced by AIPL1 Variations as a Cause of Leber Congenital Amaurosis." Investigative ophthalmology & visual science vol. 56,13 (2015): 7784-7793. doi: https://doi.org/10.1167/iovs.15-18092
Bellingham J, Davidson AE, Aboshiha J, Simonelli F, Bainbridge JW, Michaelides M, van der Spuy J. Investigation of Aberrant Splicing Induced by AIPL1 Variations as a Cause of Leber Congenital Amaurosis. Invest Ophthalmol Vis Sci. 2015 Dec 01;56(13):7784-7793. doi: 10.1167/iovs.15-18092. PMID: 26650897.
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Invest Ophthalmol Vis Sci. 2015 Dec 01;56(13):7784-7793. doi: 10.1167/iovs.15-18092.

Investigation of Aberrant Splicing Induced by AIPL1 Variations as a Cause of Leber Congenital Amaurosis.

Investigative ophthalmology & visual science

James Bellingham, Alice E Davidson, Jonathan Aboshiha, Francesca Simonelli, James W Bainbridge, Michel Michaelides, Jacqueline van der Spuy

Affiliations

  1. UCL Institute of Ophthalmology London, United Kingdom.
  2. UCL Institute of Ophthalmology London, United Kingdom 2Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.
  3. Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Second University of Naples, Naples, Italy.

PMID: 26650897 DOI: 10.1167/iovs.15-18092

Abstract

PURPOSE: Biallelic mutations in AIPL1 cause Leber congenital amaurosis (LCA), a devastating retinal degeneration characterized by the loss or severe impairment of vision within the first few years of life. AIPL1 is highly polymorphic with more than 50 mutations and many more polymorphisms of uncertain pathogenicity identified. As such, it can be difficult to assign disease association of AIPL1 variations. In this study, we investigate suspected disease-associated AIPL1 variations, including nonsynonymous missense and intronic variants to validate their pathogenicity.

METHODS: AIPL1 minigenes harboring missense and intronic variations were constructed by amplification of genomic fragments of the human AIPL1 gene. In vitro splice assays were performed to identify the resultant AIPL1 transcripts.

RESULTS: We show that all nine of the suspected disease-associated AIPL1 variations investigated induced aberrant pre-mRNA splicing of the AIPL1 gene, and our study is the first to show that AIPL1 missense mutations alter AIPL1 splicing. We reveal that the presumed rare benign variant c.784G>A [p.(G262S)] alters in vitro AIPL1 splicing, thereby validating the disease-association and clarifying the underlying disease mechanism. We also reveal that in-phase exon skipping occurs normally at a low frequency in the retina, but arises abundantly as a consequence of specific AIPL1 variations, suggesting a tolerance threshold for the expression of these alternative transcripts in the retina normally, which is exceeded in LCA.

CONCLUSIONS: Our data confirm the disease-association of the AIPL1 variations investigated and reveal for the first time that aberrant splicing of AIPL1 is an underlying mechanism of disease in LCA.

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