May 2004
Volume 45, Issue 13
ARVO Annual Meeting Abstract  |   May 2004
ABCA4 Mutational Analysis in a Cohort of 30 Recessive Retinitis Pigmentosa Families
Author Affiliations & Notes
  • C.M. Zaremba
    Molec/Human Genetics, Baylor College Medicine, Houston, TX
  • A. Yatsenko
    Molec/Human Genetics, Baylor College Medicine, Houston, TX
  • W. Wiszniewski
    Molec/Human Genetics, Baylor College Medicine, Houston, TX
  • M. Leppert
    Dept of Human Genetics, Univ of Utah, Salt Lake City, UT
  • R. Lewis
    Molec/Human Genetics, Baylor College Medicine, Houston, TX
  • J. Lupski
    Molec/Human Genetics, Baylor College Medicine, Houston, TX
  • Footnotes
    Commercial Relationships  C.M. Zaremba, None; A. Yatsenko, None; W. Wiszniewski, None; M. Leppert, None; R. Lewis, None; J. Lupski, None.
  • Footnotes
    Support  NIH Grant EY013255–02
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 5090. doi:
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      C.M. Zaremba, A. Yatsenko, W. Wiszniewski, M. Leppert, R. Lewis, J. Lupski; ABCA4 Mutational Analysis in a Cohort of 30 Recessive Retinitis Pigmentosa Families . Invest. Ophthalmol. Vis. Sci. 2004;45(13):5090.

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

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Abstract: : Purpose: Retinitis Pigmentosa (RP) represents a genetically heterogeneous (>30 genes) group of inherited disorders which lead to complete loss of vision. Among the causative RP genes known, null mutations in ABCA4 (ABCR), a gene whose products transport function has yet to be fully elucidated, are of interest as they may provide more insight regarding its function. Genetic analyses and diagnoses of disorders associated with ABCA4 alterations have been confounded due to the large size of the gene and heterogeneity of ABCA4 variants (∼400 known). The purpose of this study was to identify ABCA4 alterations in a cohort of arRP (autosomal recessive RP) families. Methods: To resolve these challenges we employed the use of a commercially available ABCA4 genotyping microarray chip (ABCR–400, ASPER) to screen ABCA4 alterations in the coding regions of a cohort of 30 arRP families. ABCA4 regulatory and non–coding regions were not available for screening. Confirmation of this study was carried out via direct sequencing and segregation analysis. Results: We identified 10 out of 60 (∼17%) alleles with ABCA4 alterations. Interestingly, two arRP families with two distinct ABCA4 disease alleles cosegregated with RP. In the first family, a complex allele comprising a mild alteration, L541P, with a severe alteration, A1038V, was found in two arRP patients. In the second family, a severe truncating allele, R408X, was identified with a missense alteration, R602W. Splice site mutations, 36IVS+1 and V2050L, considered to be disease alleles, were identified in two families. Single missense alterations, including the mild G1961E (1/60; 1.7%) and D2177N (2/60; 3.3%) alleles associated with age–related macular degeneration, and P68L (1/60; 1.7%) were identified. Segregation analyses of these affected families were performed but were not informative. Conclusions: This represents the first comprehensive genetic study of the influence of ABCA4 alterations on recessive RP. We have demonstrated a higher frequency (17%) of ABCA4 alterations in arRP patients than expected by chance. Of those alterations, 6/10 (60%) alleles are presumed to have an important role in arRP. Of these ABCA4 alterations, one family demonstrated compound homozygousity for the complex allele [L541P; A1038V], suggesting a possible synergistic affect between the mild alteration, L541P, and the severe alteration, A1038V. However, 4/10 (40%) alleles may have mild or neutral effects on ABCR function. These data confirm that ABCA4 alterations can have a role in the pathogenesis of arRP.

Keywords: retina • retina: distal (photoreceptors, horizontal cells, bipolar cells) • gene screening 

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