ESPE Yearbook of Paediatric Endocrinology

Hum Genet. 2021 Nov;140(11):1553-1562. doi: 10.1007/s00439-021-02259-2.

Brief Summary: This paper describes 5 related Karelian Bear Dogs (KBDs) with a canine hypopituitarism phenotype. Genome-wide association analysis (GWAS) and next-generation sequencing revealed a homozygous candidate gene defect in POU1F1. The study thus presents a novel animal model for human hypopituitarism.

In addition to humans, hypopituitarism can spontaneously occur in animals, including mice and dogs. In dogs, hypopituitarism has been reported in German Shepherds and KBDs. The affected dogs of both breeds manifest with small size and puppy coats with hair loss (1, 2). The German Shepherds have deficiencies of growth hormone, thyroid-stimulating hormone, gonadotropins, and prolactin due to a recessive splicing variant in LHX3 (1, 3), whereas the KBDs have low insulin-like growth factor 1 levels and a suggested autosomal recessive disease (2).

Here, the authors describe 5 related KBDs, who were suspected of hypopituitarism based on their size and coat. In addition, 1 of these dogs had a low level of insulin-like growth factor and 1 had hypothyroidism. GWAS using SNP array data, performed in the 5 affected cases and 139 KBD controls, mapped the disease locus to chromosome 31, where the affected dogs shared allelic homozygosity. Whole genome sequencing on 3 affected dogs filtered the best candidate gene to a homozygous intronic variant in the gene, POU1F1. The variant was predicted to affect gene splicing and it was heterozygous or absent in 1035 control genomes or exomes of various breeds.

Genotyping the variant in a cohort of 642 KBDs, including the affected cases and their available close relatives, revealed 62 heterozygotes and 3 additional homozygous individuals, 1 of which was still alive and manifested a hypopituitarism phenotype. Furthermore, 7 Lapponian Herders harboring the POU1F1 variant were identified among 349 dogs of related breeds and 1 heterozygote KBD among 7925 dogs from 206 different breeds, indicating high KBD breed-specificity of the POU1F1 variant.

To conclude, this paper suggests that a rare homozygous defect in POU1F1 can underlie hypopituitarism not only in humans (4) but also in dogs. However, future efforts are needed to comprehensively evaluate the canine hormone deficiencies and show the functional effect of the variant on splicing.

References: 1. Kooistra HS, Voorhout G, Mol JA, Rijnberk A. Combined pituitary hormone deficiency in german shepherd dogs with dwarfism. Domest Anim Endocrinol 2000 19(3):177–190. 2. Andresen E, Willeberg P. Pituitary dwarfism in Carelian bear-dogs: evidence of simple, autosomal recessive inheritance. Hereditas 1977 84(2):232–234. 3. Voorbij AM, van Steenbeek FG, Vos-Loohuis M, Martens EE, Hanson-Nilsson JM, van Oost BA, Kooistra HS, Leegwater PA. A contracted DNA repeat in LHX3 intron 5 is associated with aberrant splicing and pituitary dwarfism in German shepherd dogs. PLoS One 2011 6(11):e27940. 4. Jadhav S, Diwaker C, Lila AR, Gada JV, Kale S, Sarathi V, Thadani PM, Arya S, Patil VA, Shah NS, Bandgar TR. POU1F1 mutations in combined pituitary hormone deficiency: differing spectrum of mutations in a Western-Indian cohort and systematic analysis of world literature. Pituitary 2021 Oct;24(5):657–669.