Abstract
A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD) in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse “knock-in” model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct.
Highlights
Late-onset retinal macular degeneration (L-ORMD) is a fully penetrant autosomal dominant disorder associated with a lateonset macular degeneration resembling age-related macular degeneration (AMD) [1,2,3]
Serine is encoded by an AGC codon, the same point mutation (AGC.AGG) in mouse C1qtnf5 introduces the mutation found in L-ORMD patients
These were initially screened by polymerase chain reaction (PCR) amplification, which identified 10 potentially targeted clones, which were further characterised by PCR, Southern blotting and sequencing
Summary
Late-onset retinal macular degeneration (L-ORMD) is a fully penetrant autosomal dominant disorder associated with a lateonset macular degeneration resembling age-related macular degeneration (AMD) [1,2,3]. L-ORMD shows disease onset in the fifth to sixth decade with impaired dark adaptation associated with both punctate and diffuse sub-retinal pigment epithelium (RPE) deposits, leading to central and later peripheral visual loss and, at late stages, a pan-retinal atrophy often with choroidal neovascularisation (CNV) and disciform scarring. The most striking and consistent pathological feature is a thick (#50 mm) extracellular sub-RPE deposit, worst in the macula but extending to the extreme retinal periphery [2,3]. The deposits resemble basal laminar deposits that can be seen both in aged and in AMD eyes, with wide-spaced collagen, RPE basal processes penetrating the deposits and appearances consistent with exocytosis of packets of fibrillar material into the deposits [3].
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