ABCA4 p.Trp41*
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c.122G>A
,
p.Trp41*
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, not provided
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[hide] ABCA4 disease progression and a proposed strategy ... Hum Mol Genet. 2009 Mar 1;18(5):931-41. Epub 2008 Dec 12. Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, Roman AJ, Sumaroka A, Steinberg JD, Jacobson SG, Stone EM, Palczewski K
ABCA4 disease progression and a proposed strategy for gene therapy.
Hum Mol Genet. 2009 Mar 1;18(5):931-41. Epub 2008 Dec 12., [PMID:19074458]
Abstract [show]
Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene replacement therapy. All individuals with ABCA4-disease show macular degeneration, but only some are thought to progress to retina-wide blindness. It is currently not predictable if or when specific ABCA4 genotypes will show extramacular disease, and how fast it will progress thereafter. Early clinical trials of focal subretinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals with known disease-causing ABCA4 alleles, we defined retina-wide disease expression by measuring rod- and cone-photoreceptor-mediated vision. Serial measurements over a mean period of 8.7 years were consistent with a model wherein a normal plateau phase of variable length was followed by initiation of retina-wide disease that progressed exponentially. Once initiated, the mean rate of disease progression was 1.1 log/decade for rods and 0.45 log/decade for cones. Spatio-temporal progression of disease could be described as the sum of two components, one with a central-to-peripheral gradient and the other with a uniform retina-wide pattern. Estimates of the age of disease initiation were used as a severity metric and contributions made by each ABCA4 allele were predicted. One-third of the non-truncating alleles were found to cause more severe disease than premature truncations supporting the existence of a pathogenic component beyond simple loss of function. Genotype-based inclusion/exclusion criteria and prediction of the age of retina-wide disease initiation will be invaluable for selecting appropriate candidates for clinical trials in ABCA4 disease.
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No. Sentence Comment
50 P3 (W41X/R1098C) progressed from normal sensitivity (3.1 dB loss) at age 19 to a loss of 12.5 dB at age 27.
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ABCA4 p.Trp41* 19074458:50:4
status: NEW153 c Nt, amino-terminal domain; ECD-1 and ECD-2, exocytoplasmic domains 1 and 2; NBD-1 and NBD-2, nucleotide binding domains 1 and 2; TM5, TM6, TM7, TM12, within, near or between transmembrane helices 5, 6, 7 and 12. d W41X, R152X, Y245X, Y362X, W663X, M669del2tccAT, R681X and A1739 del11gcTGGGCTGGTGG. retina-wide blindness, the quality of life deteriorates dramatically with loss of mobility and independence.
X
ABCA4 p.Trp41* 19074458:153:216
status: NEW