An analysis of allelic variation in the ABCA4 gene

A. R. Webster, E. Héon, A. J. Lotery, K. Vandenburgh, T. L. Casavant, K. T. Oh, G. Beck, G. A. Fishman, B. L. Lam, A. Levin, J. R. Heckenlively, S. G. Jacobson, Richard Weleber, V. C. Sheffield, E. M. Stone

Research output: Contribution to journalArticle

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Abstract

Purpose. To assess the allelic variation of the ATP-binding transporter protein (ABCA4). Methods. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. Results. There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P <0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. Conclusions. Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).

Original languageEnglish (US)
Pages (from-to)1179-1189
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume42
Issue number6
StatePublished - 2001
Externally publishedYes

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Amino Acid Substitution
Penetrance
Macular Degeneration
Genes
DNA Sequence Analysis
Codon
Carrier Proteins
Nucleotides
Adenosine Triphosphate
Alleles
DNA
Stargardt disease 1

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Webster, A. R., Héon, E., Lotery, A. J., Vandenburgh, K., Casavant, T. L., Oh, K. T., ... Stone, E. M. (2001). An analysis of allelic variation in the ABCA4 gene. Investigative Ophthalmology and Visual Science, 42(6), 1179-1189.

An analysis of allelic variation in the ABCA4 gene. / Webster, A. R.; Héon, E.; Lotery, A. J.; Vandenburgh, K.; Casavant, T. L.; Oh, K. T.; Beck, G.; Fishman, G. A.; Lam, B. L.; Levin, A.; Heckenlively, J. R.; Jacobson, S. G.; Weleber, Richard; Sheffield, V. C.; Stone, E. M.

In: Investigative Ophthalmology and Visual Science, Vol. 42, No. 6, 2001, p. 1179-1189.

Research output: Contribution to journalArticle

Webster, AR, Héon, E, Lotery, AJ, Vandenburgh, K, Casavant, TL, Oh, KT, Beck, G, Fishman, GA, Lam, BL, Levin, A, Heckenlively, JR, Jacobson, SG, Weleber, R, Sheffield, VC & Stone, EM 2001, 'An analysis of allelic variation in the ABCA4 gene', Investigative Ophthalmology and Visual Science, vol. 42, no. 6, pp. 1179-1189.
Webster AR, Héon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT et al. An analysis of allelic variation in the ABCA4 gene. Investigative Ophthalmology and Visual Science. 2001;42(6):1179-1189.
Webster, A. R. ; Héon, E. ; Lotery, A. J. ; Vandenburgh, K. ; Casavant, T. L. ; Oh, K. T. ; Beck, G. ; Fishman, G. A. ; Lam, B. L. ; Levin, A. ; Heckenlively, J. R. ; Jacobson, S. G. ; Weleber, Richard ; Sheffield, V. C. ; Stone, E. M. / An analysis of allelic variation in the ABCA4 gene. In: Investigative Ophthalmology and Visual Science. 2001 ; Vol. 42, No. 6. pp. 1179-1189.
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abstract = "Purpose. To assess the allelic variation of the ATP-binding transporter protein (ABCA4). Methods. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. Results. There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P <0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. Conclusions. Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35{\%} of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).",
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T1 - An analysis of allelic variation in the ABCA4 gene

AU - Webster, A. R.

AU - Héon, E.

AU - Lotery, A. J.

AU - Vandenburgh, K.

AU - Casavant, T. L.

AU - Oh, K. T.

AU - Beck, G.

AU - Fishman, G. A.

AU - Lam, B. L.

AU - Levin, A.

AU - Heckenlively, J. R.

AU - Jacobson, S. G.

AU - Weleber, Richard

AU - Sheffield, V. C.

AU - Stone, E. M.

PY - 2001

Y1 - 2001

N2 - Purpose. To assess the allelic variation of the ATP-binding transporter protein (ABCA4). Methods. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. Results. There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P <0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. Conclusions. Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).

AB - Purpose. To assess the allelic variation of the ATP-binding transporter protein (ABCA4). Methods. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. Results. There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P <0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. Conclusions. Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).

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