An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease

Abstract

was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in 35

Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations

“…The affected animals, homozygous for the deleterious, c.4176insC, p.(Phe1393Leufs*2), allele presented with a phenotype more closely resembling the ABCA4 -associated retinopathy in humans ( Makelainen et al, 2019 ), including visual impairment at 10 years of age, abnormal fundus images, a complete loss of ABCA4 protein, profound reduction of cone outer segments, and an approximately 50% reduction of photoreceptor nuclei in the affected retinae. The RPE autofluorescence in the affected animal, indicating lipofuscin accumulation, was ~7X higher compared to the unaffected dogs and a clear functional defect was detected by flash-electroretinography ( Makelainen et al, 2019 ). In summary, the dogs with no functional ABCA4 closely resembled the human phenotype, although the disease severity was still less profound than in patients lacking ABCA4 ( Tanaka et al., 2018 ).…”

“…The best published resolution of the native ABCA4 protein and some mutants, is 18 Å ( Tsybovsky et al, 2010 , 2013 ; Tsybovsky and Palczewski, 2014 ). The lack of high-resolution ABCA4 structure makes functional studies challenging, limiting experimental systems to animal models ( Makelainen et al, 2019 ; Molday et al, 2018 ; Molday and Molday RS, 2016 ; Zhang et al, 2015 ) and in vitro assays, including ATP binding, ATPase activity and vesicular transport studies ( Ahn and Molday, 2000 ; Beharry et al, 2004 ; Sun et al, 1999 ). The current status of the structure and (biochemical) function of ABCA4 protein is outside of the scope of this review.…”

“…As such, extensive efforts over the last 20 years have been devoted to identify a more suitable model system, such as certain breeds of dogs, which have a macula-like “visual streak” that have been efficiently used to study severe retinal degenerations resulting from mutations in the RPE65 gene ( Acland et al, 2001 ; Jacobson et al, 2005 ) and among others. While the existence of a dog with ABCA4 -associated retinopathy was very likely due to the extensive genetic variability not only in the human ABCA4 locus but also in other mammals, the search was successful only very recently, when when several Labrador retrievers were identified and characterized as a KO for ABCA4 ( Makelainen et al, 2019 ). The affected animals, homozygous for the deleterious, c.4176insC, p.(Phe1393Leufs*2), allele presented with a phenotype more closely resembling the ABCA4 -associated retinopathy in humans ( Makelainen et al, 2019 ), including visual impairment at 10 years of age, abnormal fundus images, a complete loss of ABCA4 protein, profound reduction of cone outer segments, and an approximately 50% reduction of photoreceptor nuclei in the affected retinae.…”

“…While the existence of a dog with ABCA4 -associated retinopathy was very likely due to the extensive genetic variability not only in the human ABCA4 locus but also in other mammals, the search was successful only very recently, when when several Labrador retrievers were identified and characterized as a KO for ABCA4 ( Makelainen et al, 2019 ). The affected animals, homozygous for the deleterious, c.4176insC, p.(Phe1393Leufs*2), allele presented with a phenotype more closely resembling the ABCA4 -associated retinopathy in humans ( Makelainen et al, 2019 ), including visual impairment at 10 years of age, abnormal fundus images, a complete loss of ABCA4 protein, profound reduction of cone outer segments, and an approximately 50% reduction of photoreceptor nuclei in the affected retinae. The RPE autofluorescence in the affected animal, indicating lipofuscin accumulation, was ~7X higher compared to the unaffected dogs and a clear functional defect was detected by flash-electroretinography ( Makelainen et al, 2019 ).…”

Pathogenic Mechanisms Underlying Stargardt Macular Degeneration Linked to Mutations in the Transmembrane Domains of ABCA4

“…Loss of ABCA4 transport activity results in the formation and accumulation of bisretinoids including A2E in photoreceptors and RPE cells (Sparrow and Boulton 2005). These compounds accumulate as fluorescent liposfuscin deposits in STGD1 patients and animal models harboring ABCA4 null alleles and loss of function mutations (Weng, Mata et al 1999, Mata, Weng et al 2000, Boyer, Higbee et al 2012, Burke, Duncker et al 2014, Zhang, Tsybovsky et al 2015, Molday, Wahl et al 2018, Makelainen, Godia et al 2019. To date, however, the pathogenic mechanisms by which mutations in the TMDs of ABCA4 cause STGD1 have not been addressed in detail.…”