FAN1 Deletion Variant in Basenji Dogs with Fanconi Syndrome

Area of Science:

• Canine genetics
• Renal physiology
• Molecular biology

Background:

• Fanconi syndrome is a kidney tubule transport disorder with acquired and hereditary forms.
• A late-onset, inherited form affects Basenjis, hindering eradication through selective breeding.
• Identifying the genetic basis is crucial for developing screening tests.

Purpose of the Study:

• To identify the molecular genetic cause of Fanconi syndrome in Basenjis.
• To enable genetic screening for early detection and prevention of affected offspring.
• To elucidate the underlying genetic defect for better disease understanding.

Main Methods:

• Genome-wide linkage analysis in Basenji families to map the disease locus.
• Fine mapping to narrow down the candidate region on canine chromosome 3 (CFA3).
• Whole-genome sequencing of affected Basenjis and analysis of homozygous variants within the mapped region.

Main Results:

• A significant linkage was found between CFA3 markers and the Fanconi syndrome phenotype.
• A homozygous 317 bp deletion in the FAN1 gene's last exon was identified in affected dogs.
• Genotyping revealed high concordance between the FAN1 deletion and the disease, with one exception.

Conclusions:

• The study strongly suggests FAN1 deficiency causes Fanconi syndrome in Basenjis.
• FAN1's DNA repair function implies kidney cell sensitization to DNA damage as a potential mechanism.
• Further research is needed to understand the exact disease mechanism and variability in onset.