TY - JOUR
T1 - The effect on retinal structure and function of 15 specific ABCA4 mutations
T2 - A detailed examination of 82 Hemizygous patients
AU - Fakin, Ana
AU - Robson, Anthony G.
AU - Chiang, John Pei Wen
AU - Fujinami, Kaoru
AU - Moore, Anthony T.
AU - Michaelides, Michel
AU - Holder, Graham E.
AU - Webster, Andrew R.
N1 - Publisher Copyright:
© 2016, Association for Research in Vision and Ophthalmology Inc. All rights reserved.
PY - 2016/11
Y1 - 2016/11
N2 - PURPOSE. To determine the effect of 15 individual ABCA4 mutations on disease severity. METHODS. Eighty-two patients harboring 15 distinct ABCA4 mutations in trans with null (hemizygous), 10 homozygous, and 20 nullizygous patients were recruited. Age of onset was determined from medical histories. Electroretinography (ERG) responses were classified into three groups (normal; cone dysfunction; cone and rod dysfunction). The dark-adapted brightflash (DA 10.0) a-wave amplitudes and the light-adapted flicker ERG (LA 3.0 30 Hz) amplitudes were plotted against age and compared with the nullizygous patients. Fundus autofluorescence imaging (FAF) was assessed when available. RESULTS. Patients hemizygous for p.G1961E and p.R2030Q had normal ERGs. Patients harboring p.R24H, p.R212C, p.G863A/delG, p.R1108C, p.P1380L, p.L2027F, and c.5714+5G>A had abnormal ERGs (ERG group 2 or 3) at older ages, in most cases with significantly higher amplitudes than nullizygous patients. Mutations p.L541P+A1038V, p.E1022K, p.C1490Y, p.E1087K, p.T1526M, and p.C2150Y were associated with abnormal ERGs (group 2 or 3) and amplitudes comparable to those of nullizygous patients. The majority of patients, including those harboring p.G1961E, had foveal atrophy; while both patients harboring p.R2030Q had foveal sparing. Most patients harboring intermediate and null-like mutations displayed FAF abnormalities extending beyond the vascular arcades. CONCLUSIONS. In the hemizygous state, 2/15 ABCA4 alleles retain preserved peripheral retinal function; 7/15 are associated with either preserved or only mildly abnormal retinal function, worse in older patients; 6/15 behave like null mutations. These data help characterize the degree of dysfunction conferred by specific mutant ABCA4 proteins in the human retina.
AB - PURPOSE. To determine the effect of 15 individual ABCA4 mutations on disease severity. METHODS. Eighty-two patients harboring 15 distinct ABCA4 mutations in trans with null (hemizygous), 10 homozygous, and 20 nullizygous patients were recruited. Age of onset was determined from medical histories. Electroretinography (ERG) responses were classified into three groups (normal; cone dysfunction; cone and rod dysfunction). The dark-adapted brightflash (DA 10.0) a-wave amplitudes and the light-adapted flicker ERG (LA 3.0 30 Hz) amplitudes were plotted against age and compared with the nullizygous patients. Fundus autofluorescence imaging (FAF) was assessed when available. RESULTS. Patients hemizygous for p.G1961E and p.R2030Q had normal ERGs. Patients harboring p.R24H, p.R212C, p.G863A/delG, p.R1108C, p.P1380L, p.L2027F, and c.5714+5G>A had abnormal ERGs (ERG group 2 or 3) at older ages, in most cases with significantly higher amplitudes than nullizygous patients. Mutations p.L541P+A1038V, p.E1022K, p.C1490Y, p.E1087K, p.T1526M, and p.C2150Y were associated with abnormal ERGs (group 2 or 3) and amplitudes comparable to those of nullizygous patients. The majority of patients, including those harboring p.G1961E, had foveal atrophy; while both patients harboring p.R2030Q had foveal sparing. Most patients harboring intermediate and null-like mutations displayed FAF abnormalities extending beyond the vascular arcades. CONCLUSIONS. In the hemizygous state, 2/15 ABCA4 alleles retain preserved peripheral retinal function; 7/15 are associated with either preserved or only mildly abnormal retinal function, worse in older patients; 6/15 behave like null mutations. These data help characterize the degree of dysfunction conferred by specific mutant ABCA4 proteins in the human retina.
KW - ABCA4
KW - Electrophysiology
KW - Fundus autofluorescence
KW - Inherited retinal disease
KW - Retinal dystrophy
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U2 - 10.1167/iovs.16-20446
DO - 10.1167/iovs.16-20446
M3 - Article
C2 - 27820952
AN - SCOPUS:84994759841
SN - 0146-0404
VL - 57
SP - 5963
EP - 5973
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 14
ER -