Medical Applications of Sequence Walkers:
ABCR Mutation G863A

Sequence of the ABCR gene and a mutated sequence at the
5' end of exon 17.  The top one has a G which is the middle
base of the codon GGA, coding for G (glycine).  The bottom
sequence shows this base changed to a C, GCA now coding for
A (Alanine).  Below the top sequence are two sequence
walkers for human splice acceptor sites of 11.6 bits
(exactly at the end of the exon) and 3.9 bits (3 bases to
the left end of the exon).  After the mutation the first
walker becomes 9.7 bits and the second one becomes 9.8 bits.

The ABCR protein is a putative retinoid transporter in rod photoreceptor cells, alterations in which cause numerous inherited eye diseases. A G to C mutation at position 366 (arrow) of the ABCR gene is responsible for Stargardt disease and is involved in age-related macular degeneration. The mutation changes a glycine to an alanine in exon 17, but in addition the change is at a splice acceptor site. A model of human splice acceptors built using information theory was used to identify acceptor sites in this region. The acceptor sites are shown by horizontal sets of letters called sequence walkers (Nucl. Acids Res., 25: 4408-4415, 1997). There is a strong 11.6 bit acceptor at the end of exon 17 of the wild type sequence (top) and a relatively weak cryptic acceptor of 3.9 bits 3 bases downstream. In the mutant sequence (bottom), the 11.6 bit acceptor has been degraded to 9.7 bits while the 3.9 bit cryptic acceptor has been increased to 9.8 bits. The two acceptors probably compete equally well for spliceosome binding, so that the mutation either causes a missense (G863A) or a deletion of the amino acid due to activation of the cryptic acceptor. See and for further information.

Rando Allikmets, Wyeth W. Wasserman, Amy Hutchinson, Philip Smallwood, Jeremy Nathans, Peter K. Rogan, Thomas D. Schneider, Michael Dean, Organization of the ABCR gene: analysis of promoter and splice junction sequences, Gene (215)1: 111-122 , 1998.

2000 February 20: The prediction was correct! A paper was published in which the authors measured the amount of RNA and the two forms were observed: Maugeri et al. Am J Hum Genet 1999 Apr;64(4):1024-1035. The citation and abstract are available at pubmed and at AJHG.

This patented technology is available through a web server, the Automated Splice Site Analysis server by Pete Rogan's group. Further documentation is available in their paper Automated splicing mutation analysis by information theory and on the page Automated Splice Site Analysis. More than 100 papers have been published using this server. This server is recommended by the American College of Medical Genetics.

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Schneider Lab

origin: 1998 May 21
updated: 2008 Nov 20
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