Whole genome sequencing reveals a deletion of the last exon of FAN1 in Basenji dogs with adult-onset Fanconi syndrome. G. S. Johnson1, F. H. Farias1, T. Mhlanga-Mutangadura1, J. F. Taylor2, D. P. O'Brien3, R. D. Schnabel2 1) Department of Veterinary Pathobiology, University of Missouri, Columbia, MO; 2) Division of Animal Sciences, University of Missouri, Columbia, MO; 3) Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO.
Fanconi Syndrome (FS) is a generalized proximal tubule reabsorption deficiency, characterized by metabolic acidosis, amino aciduria, glucosuria, and phosphaturia. An autosomal recessive, adult-onset FS occurs in Basenji dogs. Linkage analysis and homozygosity mapping restricted the FS locus to 2.7 Mb of CFA3 containing 16 genes. We used NextGen sequencing technology (Illumina GAIIx and Hi-Seq 2000) to generate a 12.4-fold coverage whole genome sequence of a Basenji affected with FS. The reads were aligned to the canine genome reference sequence (build 2.1) with NextGENe software (SoftGenetics). None of the 244 annotated exons within the targeted region contained credible causal sequence variants; however, 16 exons fell partially or completely within gaps in the aligned basenji sequence, mostly associated with high G-C content. We therefore compared the depth-of-coverage profiles for the affected basenji sequence to profiles from similarly generated whole-genome sequences from 3 other dogs with different heritable diseases. A unique 334 bp gap was detected in the Basenji sequence. Sanger sequencing across the gap revealed a 321 bp deletion which included the last exon of FAN1. Homozygosity for the deletion allele was strongly associated with FS in a cohort of basenjis. The FAN1 gene symbol stands for Fanconi-anemia Associated Nuclease 1, so named because its encoded protein, FAN1, interacts with components of the Fanconi anemia (FA) pathway for DNA-crosslink repair. FA and FS are two seemingly distinct diseases referred to with eponyms honoring Swiss pediatrician Guido Fanconi. The last exon of FAN1 encodes part of a VRR-NUC nuclease domain, believed to be of functional importance. We here report that canine FAN1 deficiency causes FS, not FA as predicted by others based on previous cell culture experiments. If FAN1 deficiency is found to cause FS in additional species, the name of the gene can be changed to Fanconi-syndrome Associated Nuclease 1 without a gene symbol change.
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