Genotyping for a variant in SLC13A1 - results of an IVDD research study

The following report was prepared by Dr Cathryn Mellersh of the Kennel Club's Genetics Centre. Dachshund Health UK funded a study looking at SLC13A1. We gratefully acknowledge this work done by Cathryn and her team.

Recently, Professor Paul Freeman, who leads the Cambridge IVDD Research Group, was contacted by

a human rheumatologist, who described a mutation in a gene called SLC13A1 which caused

significant IVDD in the affected person. Variants in the same gene have previously been described

as a cause of severe chondrodysplasia in a Miniature Poodles and Texel sheep. Mutations cause

excessive sulphate excretion through the kidneys, which leads to proteins being affected and hence

the potential effects on discs, amongst other things.

As a result, KCGC staff looked for variants in SLC13A1 within their database of whole genome

sequences from over 200 dogs; they found just four variants within SLC13A1 in all the dogs they

examined, and one of those dogs was a Dachshund. The Dachshund’s variant was ‘private’ meaning

it wasn’t found in any other dogs (so it is very rare). The KCGC sequenced the genome of this

Dachshund because it was affected with a potentially inherited eye disease, and we don’t know

whether it also had IVDD. But the fact that it carries a very rare variant in an IVDD candidate gene

raised the possibility that this variant/gene could potentially have an influence on IVDD.

We therefore proceeded to genotype the same variant in DNA from 63 IVDD affected Dachshunds,

(affected group) and 64 dogs which reached at least 10 years of age without being affected (control

group).

The results were as follows:

	GG	GC
IVDD cases	62	1 (MLHD)
IVDD controls	59	5 (4 MLHD; 1 MSHD)

G is the wildtype/reference nucleotide and C is the variant.

The variant was slightly more frequent among the IVDD controls than the cases, but the results were

not statistically significant, and at this stage do not provide evidence to support the hypothesis that

SLC13A1 might be an IVDD candidate gene.

However, the variant we genotyped was chosen because it was rare among dogs, and possibly is

‘private’ to Dachshunds; we did not have any evidence that it is deleterious in anyway or is in fact

associated with IVDD. It was a good place to start but at this stage we do not have enough evidence

to include SLC13A1 as an IVDD candidate gene.

Future work

The KCGC has submitted DNA from four MSHD (three IVDD cases and one control) for whole genome

sequencing (WGS). Once we have the WGS data we will be able to look at the entire SLC13A1 gene

sequence in these dogs of known IVDD status to identify any additional variants that might be

deleterious, and that associate with IVDD. Any potential candidate variants we identify could then be

genotyped in the larger cohort of IVDD cases and controls described above, to further investigate

the role of IVDD in Dachshunds.

The KCGC is also applying for funding to undertake a larger genetic investigation of IVDD in Dachshunds, Cocker Spaniels and French Bulldogs, all of which are at increased risk of IVDD compared to other breeds. If the funding application is successful they will generate WGS from additional IVDD cases and controls from all three breeds and undertake a large-scale investigation aimed at identifying

genetic risk variants in addition to 12-FGF4RG that has been described previously.

DHUK will also be making a grant to support a Masters project starting in October at Cambridge Vet School. Poly (ADP-Ribose) or PAR has been shown to have an integral role in the process of calcification of other soft tissues eg vascular tissues, and we expect that it is also plays an important role in intervertebral disc calcification in dogs. PAR is also a known marker of apoptosis and has been used

as such in intervertebral disc degeneration in humans. This new project will investigate the role of PAR and apoptotic mediators in canine disc degeneration and calcification.

If you would like to support our IVDD research with a donation, you can do so here.