Identification of genetic variation and haplotype structure of the canine ABCA4 gene for retinal disease association studies

Abstract

Over 200 mutations in the retina specific member of the ATP-binding cassette transporter superfamily (ABCA4) have been associated with a diverse group of human retinal diseases. The disease mechanisms, and genotype-phenotype associations, nonetheless, remain elusive in many cases. As orthologous genes are commonly mutated in canine models of human blinding disorders, canine ABCA4 appears to be an ideal candidate gene to identify and study sequence changes in dogs affected by various forms of inherited retinal degeneration. However, the size of the gene and lack of haplotype assignment significantly limit targeted association and/or linkage approaches. This study assessed the naturally observed sequence diversity of ABCA4 in the dog, identifying 80% of novel variations. While none of the observed polymorphisms have been associated with blinding disorders to date, breed and potentially disease specific haplotypes have been identified. Moreover, a tag SNP map of 17 (15) markers has been established that accurately predicts common ABCA4 haplotypes (frequency > 5%) explaining >85% (>80%) of the observed genetic diversity and will considerably advance future studies. Our sequence analysis of the complete canine ABCA4 coding region will clearly provide a baseline and tools for future association studies and comparative genomics to further delineate the role of ABCA4 in canine blinding disorders.

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

“…The canine eye is also comparable in size to the human eye, and dog models have successfully been used for experimental gene therapy for retinal degenerative diseases, such as LCA, RP, and rod-cone dysplasia type 1 (rcd1) [ 12 , 14 , 16 , 62 ]. For over a decade there has been interest in finding a canine model for ABCA4 -mediated diseases [ 23 , 63 , 64 ]. The loss-of-function mutation identified here can be used to develop a large animal model for human STGD.…”

Next-Generation Sequencing-Aided Rapid Molecular Diagnosis of Occult Macular Dystrophy in a Chinese Family

“…Mutations in ABCA4 lead to the accumulation of toxic bisretinoid atRAL adducts of atRAL in photoreceptors and RPE ( Cideciyan et al, 2015 ), and reduced BCVA reduced as the disease process is initiated near the center of the macula ( Cideciyan et al, 2005 ; Huang et al, 2014 ). ABCA4 mutations are one of the most frequent monogenetic pathogenesis for retinal degeneration ( Cideciyan et al, 2009 , 2012 ; Zangerl et al, 2010 ; Fujinami et al, 2013 ). The clinical manifestation of ABCA4 -related retinopathy is variable, including autosomal recessive Stargardt’s disease (arSTGD), fundus flavimaculatus, autosomal recessive cone-rod dystrophy (arCRD) and autosomal RP ( Jaakson et al, 2003 ; Valverde et al, 2007 ; Riveiro-Alvarez et al, 2013 ; Jiang et al, 2016 ).…”