Version 1
: Received: 24 October 2024 / Approved: 24 October 2024 / Online: 25 October 2024 (11:54:43 CEST)
How to cite:
Katz, M. L.; Farias, F. H.; Mhlanga-Mutangadura, T.; Guo, J.; Hansen, E.; Johnson, G. S. FAN1 Deletion Variant in Basenji Dogs with Fanconi Syndrome. Preprints2024, 2024101987. https://doi.org/10.20944/preprints202410.1987.v1
Katz, M. L.; Farias, F. H.; Mhlanga-Mutangadura, T.; Guo, J.; Hansen, E.; Johnson, G. S. FAN1 Deletion Variant in Basenji Dogs with Fanconi Syndrome. Preprints 2024, 2024101987. https://doi.org/10.20944/preprints202410.1987.v1
Katz, M. L.; Farias, F. H.; Mhlanga-Mutangadura, T.; Guo, J.; Hansen, E.; Johnson, G. S. FAN1 Deletion Variant in Basenji Dogs with Fanconi Syndrome. Preprints2024, 2024101987. https://doi.org/10.20944/preprints202410.1987.v1
APA Style
Katz, M. L., Farias, F. H., Mhlanga-Mutangadura, T., Guo, J., Hansen, E., & Johnson, G. S. (2024). FAN1 Deletion Variant in Basenji Dogs with Fanconi Syndrome. Preprints. https://doi.org/10.20944/preprints202410.1987.v1
Chicago/Turabian Style
Katz, M. L., Elizabeth Hansen and Gary S. Johnson. 2024 "FAN1 Deletion Variant in Basenji Dogs with Fanconi Syndrome" Preprints. https://doi.org/10.20944/preprints202410.1987.v1
Abstract
Abstract: Fanconi syndrome is a disorder of renal proximal tubule transport characterized by metabolic acidosis, amino aciduria, glucosuria, and phosphaturia. There are acquired and hereditary forms of this disorder. Fanconi syndrome in Basenjis was first described in 1976 and is now recognized as an inherited disease in these dogs. Linkage analysis within a large family of Basenjis that included both affected and unaffected individuals was performed to localize the causative variant within the genome. Significant linkage was identified between chromosome 3 (CFA3) makers and the disease phenotype. Fine mapping restricted the region to a 2.7 Mb section of CFA3. A whole genome sequence of a Basenji affected with Fanconi syndrome was generated, and the sequence data were examined for the presence of potentially deleterious homozygous variants within the mapped region. A homozygous 317 bp deletion was identified in the last exon of FAN1 of the proband. 78 Basenjis of known disease status were genotyped for the deletion variant. Among these dogs, there was almost complete concordance between genotype and phenotype. The only exception was one dog that was homozygous for the deletion variant but did not exhibit signs of Fanconi syndrome. These data indicate that the disorder is very likely the result of FAN1 deficiency. The mechanism by which this deficiency causes the disease signs remains to be elucidated. FAN1 has endonuclease and exonuclease activity that catalyzes incisions in regions of double-stranded DNA containing interstrand crosslinks. FAN1 inactivation may cause Fanconi syndrome in Basenjis by sensitization of kidney proximal tubule cells to toxin-mediated DNA crosslinking resulting in accumulation of genomic and mitochondrial DNA damage in the kidney. Differential exposure to environmental toxins that promote DNA crosslink formation may explain the wide age-at-onset variability for the disorder in Basenjis.
Keywords
kidney; hereditary disorder; DNA repair; whole genome sequencing; toxins
Subject
Biology and Life Sciences, Biology and Biotechnology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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