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. 2017 May;95(3):240-246.
doi: 10.1111/aos.13273. Epub 2016 Oct 24.

The intronic ABCA4 c.5461-10T>C variant, frequently seen in patients with Stargardt disease, causes splice defects and reduced ABCA4 protein level

Ingvild Aukrust  1 , Ragnhild W Jansson  2   3 , Cecilie Bredrup  2 , Hilde E Rusaas  1 , Siren Berland  1 , Agnete Jørgensen  4 , Marte G Haug  5 , Eyvind Rødahl  2   3 , Gunnar Houge  1 , Per M Knappskog  1   6
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Free article

The intronic ABCA4 c.5461-10T>C variant, frequently seen in patients with Stargardt disease, causes splice defects and reduced ABCA4 protein level

Ingvild Aukrust et al. Acta Ophthalmol. 2017 May.
Free article

Abstract

Purpose: Despite being the third most common ABCA4 variant observed in patients with Stargardt disease, the functional effect of the intronic ABCA4 variant c.5461-10T>C is unknown. The purpose of this study was to investigate the molecular effect of this variant.

Methods: Fibroblast samples from patients carrying the ABCA4 variant c.5461-10T>C were analysed by isolating total RNA, followed by real-time polymerase chain reaction (RT-PCR) using specific primers spanning the variant. For detection of ABCA4 protein, fibroblast samples were lysed and analysed by SDS-PAGE followed by immunoblotting using a monoclonal ABCA4 antibody.

Results: The ABCA4 variant c.5461-10T>C causes a splicing defect resulting in the reduction of full-length mRNA in fibroblasts from patients and the presence of alternatively spliced mRNAs where exon 39-40 is skipped. A reduced level of full-length ABCA4 protein is observed compared to controls not carrying the variant.

Conclusions: This study describes the functional effect and the molecular mechanism of the pathogenic ABCA4 variant c.5461-10T>C. The variant is functionally important as it leads to splicing defects and a reduced level of ABCA4 protein.

Keywords: ABCA4; Stargardt; intronic variant; splicing.

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