In March of 2025 Canine Genetic Testing launched a DNA test for a variant associated with Primary Hyperparathyroidism in Keeshonds. And now our peer-reviewed paper, describing details of the mutation, has been published in the journal Animal Genetics (1).
Wade CM, Burmeister LM, Skelly BJ, McLaughlin B, Pettitt L, Atwater DZ, Tallmadge RL, Lejeune M, Lindblad-Toh K, Mellersh CS. Autosomal dominant primary hyperparathyroidism in the Keeshond dog breed is strongly associated with a missense variant in sirtuin-6. Anim Genet. 2025 Dec;56(6):e70056. doi: 10.1111/age.70056.
Primary hyperparathyroidism (PHPT) is a disorder of calcium metabolism. The condition occurs when either one, or (rarely) more than one of the four parathyroid glands begins to function autonomously and is not subject to feedback control due to the resulting hypercalcaemia. Parathyroid is normally secreted in response to low levels of calcium in the blood, and over production of the hormone leads to the depletion of calcium from bones and hypercalcemia in the blood.
The Keeshond is a breed that is predisposed to PHPT. Early work established that the disorder is most likely to be inherited as an autosomal dominant condition in this breed but candidate gene investigations, based on functional candidates described in human PHPT, were not able to identify a plausible mechanism (2, 3).
The newly published research, to identify the causal variant, began over 20 years ago, and has involved scientists from the UK, the United States and Australia, so this publication represents the results of a truly global collaboration.
The research first used a genome-wide association study (GWAS) to identify a region on chromosome 20 that was associated with PHPT in the Keeshond. Whole genome sequence (WGS) data were subsequently generated from two PHPT-affected and two controls Keeshonds, and the data were mined for candidate PHPT variants. The strongest candidate variant is in the SIRT6 gene. It is a missense variant, two nucleotides away from a potential splice-site donor (NC_049241.1g.55817330A>G; XM_038567756.1.c.193A>G; XP_038423684.1.p.65R>G). Both the PHPT affected Keeshonds for which we had WGS were heterozygous for this variant, and it was absent from both unaffected dogs. It was also absent from the Dog10K variant call file that included 11 Keeshonds of unknown PHPT status.
The variant changes an arginine (polar) amino acid to a glycine (non-polar) and occurs within 2 bases of a canonical splice site for exon 2 of SIRT6. SIRT6 is regarded as a multifunctional epigenetic enzyme (4) and belongs to a family of seven related members that comprise NAD+-dependent class III histone deacetylases with known impacts on organismal ageing and cardiovascular health (4). Deficiency of the Sirtuin-6 protein in osteocytes (cells that trigger bone remodelling) has been found to reduce trabecular bone volume of lumbar spine and distal femur of mice (5) and the protein is regarded as a multifunctional epigenetic enzyme (4). Given that SIRT6 has clear roles in cellular metabolism and stress responses, we hypothesize that the gene product could influence the parathyroid glands indirectly by affecting overall metabolic health and calcium homeostasis or through other epigenetic mechanisms.
DNA from 18 Keeshonds with a robust diagnosis of PHPT were all heterozygous for the SIRT6 variant, which we conclude is likely to be pathogenic, thus confirming that PHPT in this breed is inherited as an autosomal dominant condition. The fact that we did not identify any dogs that were homozygous for the variant means that either it is homozygous lethal, or that it is sufficiently uncommon in the population for homozygotes to be extremely rare.
A genetic screening test, based on the SIRT6 variant is available from Canine Genetics Testing, and will enable effective selection against PHPT in the Keeshond. We do not recommend that this test is used in any other breed currently.
References
- Wade CM, Burmeister LM, Skelly BJ, McLaughlin B, Pettitt L, Atwater DZ, et al. Autosomal dominant primary hyperparathyroidism in the Keeshond dog breed is strongly associated with a missense variant in sirtuin-6. Anim Genet. 2025;56(6):e70056.
- Goldstein RE, Atwater DZ, Cazolli DM, Goldstein O, Wade CM, Lindblad-Toh K. Inheritance, mode of inheritance, and candidate genes for primary hyperparathyroidism in Keeshonden. J Vet Intern Med. 2007;21(1):199-203.
- Thompson D, Skelly B. Prevalence of canine primary hyperparathyroidism recurrence in Keeshond and non-Keeshond dogs after curative parathyroidectomy. Vet Rec. 2020;187(11):e93.
- Ren SC, Chen X, Gong H, Wang H, Wu C, Li PH, et al. SIRT6 in Vascular Diseases, from Bench to Bedside. Aging Dis. 2022;13(4):1015-29.
- Aobulikasimu A, Liu T, Piao J, Sato S, Ochi H, Okawa A, et al. SIRT6-PAI-1 axis is a promising therapeutic target in aging-related bone metabolic disruption. Sci Rep. 2023;13(1):7991.
