Genetic Variant underlying Xanthinuria in a population of Munchkin cats

Abstract

Hereditary xanthinuria is a genetic disorder of purine metabolism causing xanthinaemia and xanthine crystalluria. Type I xanthinuria is due to mutations in xanthine dehydrogenase (XDH). Type II xanthinuria is caused by mutations in molybdenum cofactor sulfurase (MOCOS). In cats, xanthinuria is a rare but clinically significant disease; however underlying genetic variants have not been described.

Five cases of xanthinuria in Australian cats were identified, including three related Munchkin cats, one Munchkin related domestic shorthair (DSHM) and one unrelated Domestic Shorthair (DSH). An allopurinol loading test carried out in two affected Munchkin cats supported Type I xanthinuria.

Pedigree analysis suggested an autosomal recessive mode of inheritance. EDTA whole-blood samples were collected from 29 Munchkin and related DSHM cats and the unrelated affected DSH cat, and DNA extracted using a standard phenol-chloroform extraction method. Whole genome sequencing was carried out on one affected Munchkin, one suspected carrier and the unrelated affected DSH cat. Sequence reads were aligned to Felus_catus_9.0, all single nucleotide variants (SNV) and small insertions/deletions were called for XDH and MOCOS. Variants were assessed with reference to likely mode of inheritance and predicted functional impact using Polyphen2.

In the XDH gene 21 candidate causative variants were identified in XDH, including 19 exonic and two in the 5’UTR. Nine variants were synonymous, four were predicted by PolyPhen2 as benign, and five were homozygous for the reference allele in the affected Munchkin cat. A non-synonymous SNV at ChrA3:117,584,799 (XDH:c.2042C>T) was homozygous for the alternative allele in the affected DSH cat and was proposed as a candidate causative variant in this cat. In the MOCOS gene 11 exonic SNVs were identified, nine were synonymous and two predicted as benign by Polyphen2. All SNVs were excluded as the causative variant for xanthinuria in the Munchkin family.