Background

An inflammatory skin disease, exfoliative cutaneous lupus erythematosus (ECLE), is a familial form of lupus, observed in German shorthaired pointer dogs (GSP). Prior studies have confirmed an autosomal recessive mode of inheritance, as well as isolated canine chromosome 18 as the genetic component. As with several of the diseases under review by the Section of Medical Genetics at PennVet, ECLE is a translational model, having a parallel disease counterpart in human medicine; ECLE closely mimics CLE in humans, which refers to the disease as it presents in several forms. While grouped together in name, a variety of CLE manifestations differ from each other in their pathology, which is supported by the fact that a number of different responsible genes have been implicated. We have now discovered a putative gene mutation that distinguishes normal, affected, and carrier GSPs. The results are suggestive of the first direct evidence of a lupus-family disorder being related to a gene mutation. Beyond diagnostic testing to eradicate this disease from the GSP population, further study will lead to better understanding of CLE in humans and other lupus-like disorders.

ECLE GSP patients and CLE patients alike suffer from severe dermatitis. In GSPs, we observe excessive scaling skin, fluid-filled lesions, erythematic patches, and or alopecia, presenting first on the patients' head, joints, feet, and genitals. As the disease progresses, the affected surface area and severity increase, leading to secondary breaching of skin, infection, and extra-cutaneous symptoms of lameness, hunched stance, and lupus-like nephritis. Most affected dogs are euthanized before reaching 4 years of age. Sun exposure has been observed to exacerbate disease progression in both ECLE and CLE. Upon clinical observation of the disease described above, diagnosis is confirmed via histological studies. Further, our lab developed a genotyping (marker) test to confirm diagnosis of the known disease phenotype.

Objectives

To better understand and elucidate the cause of ECLE in the GSP, efforts were directed towards discovery of a gene mutation leading to the disease.

Results

Previously, we had identified that the genomic regions associated with ECLE were located on canine chromosome 18 (CFA18,) and later further narrowed the candidate area to a 0.5 MB region. After comparison to the human genome, our focus was on six genes of interest. Of these genes of interest, sequencing of DPF2 provided a SNP that was strongly associated with ECLE affected dogs (Wang et al. 2010). The single base substitution was observed on a non-coding region, intron 3 of DPF2 gene.

Further sequencing of our identified genes of interest, led to the discovery of a putative mutation, A779S (2336 G T) on the exon 14 of the signal-induced proliferation-associated protein 1 gene (SIPA1), located in chromosome 18.

Future Studies

Now that we have identified a putative mutation for ECLE, our future studies are directed towards confirming and providing additional support for our hypothesis. We hope to extrapolate and apply this knowledge to other similar diseases, most notably CLE in humans.