The Effect on Retinal Structure and Function of 15 Specific ABCA4 Mutations: A Detailed Examination of 82 Hemizygous Patients.
OBJECTIVE
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 bright-flash (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.
Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Ana
A
Fakin
Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Anthony G
AG
Robson
Casey Molecular Diagnostic Laboratory, Portland, Oregon, United States.
John Pei-Wen
JP
Chiang
Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom 4National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan 5Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan.
Kaoru
K
Fujinami
Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom 6Department of Ophthalmology, University of California-San Francisco School of Medicine, San Francisco, California, United States.
Anthony T
AT
Moore
Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Michel
M
Michaelides
Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Graham E
GE
Holder
Institute of Ophthalmology, University College London, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom.
Andrew R
AR
Webster
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012160:Retina / Q000503:physiopathology*; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology; D012162:Retinal Degeneration / Q000235:genetics / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology; D041623:Tomography, Optical Coherence; D055815:Young Adult
C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters