title: Canine genome assembly correction facilitates identification of a MAP9 deletion as a potential age of onset modifier for RPGRIP1-associated canine retinal degeneration.
abstract: Retinal degeneration (RD) in the Miniature Long Haired Dachshund (MLHD) is a cone-rod dystrophy resulting in eventual blindness in affected individuals. In a previous study, a 44-nucleotide insertion (ins44) in exon 2 of RPGRIP1 was associated with RD. However, results on an extended population of MLHD revealed a variable RD onset age for ins44 homozygous dogs. Further investigations using a genome-wide association study comparing early onset and late onset RD cases identified an age of onset modifying locus for RD, approximately 30 Mb upstream of RPGRIP1 on chr15. In this investigation, target enriched sequencing identified a MAP9 deletion spanning approximately 22 kb associated with early RD onset. Identification of the deletion required correction to the CanFam3.1 genome build as canine MAP9 is part of a historic tandem duplication, resulting in incomplete assembly of this genome region. The deletion breakpoints were identified in MAP9 intron 10 and in a downstream partial MAP9 pseudogene. The fusion of these two genes, which we have called MAP9 EORD (microtubule-associated protein, early onset retinal degeneration), is in frame and is expressed at the RNA level, with the 3' region containing several predicted deleterious variants. We speculate that MAP9 associates with α-tubulin in the basal body of the cilium. RPGRIP1 is also known to locate to the cilium, where it is closely associated with RPGR. RPGRIP1 mutations also cause redistribution of α-tubulin away from the ciliary region in photoreceptors. Hence, a MAP9 partial deficit is a particularly attractive candidate to synergise with a partial RPGRIP1 deficit to cause a more serious disease.
authors.affiliation: Kennel Club Genetics Centre, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK.
authors.forename: Oliver P
authors.initials: OP
authors.lastname: Forman
authors.affiliation: Kennel Club Genetics Centre, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK. rebekkah.hitti@aht.org.uk.
authors.forename: Rebekkah J
authors.initials: RJ
authors.lastname: Hitti
authors.affiliation: Kennel Club Genetics Centre, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Boursnell
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey St, Philadelphia, PA, 19104, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Miyadera
authors.affiliation: Comparative Genetics Group, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Rd., Cambridge, CB3 0ES, UK.
authors.forename: David
authors.initials: D
authors.lastname: Sargan
authors.affiliation: Kennel Club Genetics Centre, Animal Health Trust, Newmarket, Suffolk, CB8 7UU, UK.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Mellersh
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D005091:Exons / Q000235:genetics; D016678:Genome; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D058977:Molecular Sequence Annotation; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; C505827:MAP9 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; C415903:RPGRIP1 protein, human