Progressive retinal atrophy in Schapendoes dogs: mutation of the newly identified CCDC66 gene

• Published in: Neurogenetics 2010-05, Vol.11 (2), p.163-174
• Main Authors: Dekomien, Gabriele, Vollrath, Conni, Petrasch-Parwez, Elisabeth, Boevé, Michael H., Akkad, Denis A., Gerding, Wanda M., Epplen, Jörg T.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; DNA Mutational Analysis; Dogs; Fundamental and applied biological sciences. Psychology; Genes; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Human Genetics; Humans; Medical screening; Mice; Mice, Inbred C57BL; Molecular and cellular biology; Molecular Medicine; Molecular Sequence Data; Mutation; Neurosciences; Original Article; Polymorphism, Genetic; Protein Structure, Tertiary; Retina - pathology; Retinal Degeneration - genetics; Retinal Degeneration - pathology; Retinal Degeneration - veterinary; Sequence Alignment; Vertebrates: nervous system and sense organs
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-009-0223-z

Canine generalized progressive retinal atrophy (gPRA) is characterized by continuous degeneration of photoreceptor cells leading to night blindness and progressive vision loss. Until now, mutations in 11 genes have been described that account for gPRA in dogs, mostly following an autosomal recessive inheritance mode. Here, we describe a gPRA locus comprising the newly identified gene coiled-coil domain containing 66 ( CCDC66 ) on canine chromosome 20, as identified via linkage analysis in the Schapendoes breed. Mutation screening of the CCDC66 gene revealed a 1-bp insertion in exon 6 leading to a stop codon as the underlying cause of disease. The insertion is present in all affected dogs in the homozygous state as well as in all obligatory mutation carriers in the heterozygous state. The CCDC66 gene is evolutionarily conserved in different vertebrate species and exhibits a complex pattern of differential RNA splicing resulting in various isoforms in the retina. Immunohistochemically, CCDC66 protein is detected mainly in the inner segments of photoreceptors in mouse, dog, and man. The affected Schapendoes retina lacks CCDC66 protein. Thus this natural canine model for gPRA yields superior potential to understand functional implications of this newly identified protein including its physiology, and it opens new perspectives for analyzing different aspects of the general pathophysiology of gPRA.