Intronic variant in POU1F1 associated with canine pituitary dwarfism

Kaisa Kyöstilä,Julia E Niskanen,Jonas Donner,Marjo K Hytönen,Hannes Lohi,Meharji Arumilli

doi:10.1007/s00439-021-02259-2

Kaisa Kyöstilä, Julia E Niskanen + Show 4 more

Open Access

https://doi.org/10.1007/s00439-021-02259-2

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Abstract

The anterior pituitary gland secretes several endocrine hormones, essential for growth, reproduction and other basic physiological functions. Abnormal development or function of the pituitary gland leads to isolated or combined pituitary hormone deficiency (CPHD). At least 30 genes have been associated with human CPHD, including many transcription factors, such as POU1F1. CPHD occurs spontaneously also in mice and dogs. Two affected breeds have been reported in dogs: German Shepherds with a splice defect in the LHX3 gene and Karelian Bear Dogs (KBD) with an unknown genetic cause. We obtained samples from five KBDs presenting dwarfism and abnormal coats. A combined analysis of genome-wide association and next-generation sequencing mapped the disease to a region in chromosome 31 and identified a homozygous intronic variant in the fourth exon of the POU1F1 gene in the affected dogs. The identified variant, c.605-3C>A, resided in the splice region and was predicted to affect splicing. The variant's screening in three new prospective cases, related breeds, and ~ 8000 dogs from 207 breeds indicated complete segregation in KBDs with a carrier frequency of 8%, and high breed-specificity as carriers were found at a low frequency only in Lapponian Herders, a related breed. Our study establishes a novel canine model for CPHD with a candidate POU1F1 defect.

Highlights

The anterior pituitary gland is a critical endocrine organ composed of at least five differentiated cell types and responsible for the secretion of thyroid-stimulating hormone (TSH), growth hormone (GH), prolactin (PRL), adrenocorticotropin (ACTH), follicle-stimulating hormone (FSH) and luteinising hormone (LH) (Kerr et al 2008; de Moraes et al 2012)
In Sweden, four suspected pituitary dwarfism cases, two females and two males were reported in a litter of eight puppies
We discovered a homozygous POU1F1 variant in dogs with a clinical phenotype compatible with pituitary dwarfism; a condition reported already 45 years ago in the Karelian Bear Dogs (KBD) breed

Summary

Introduction

The anterior pituitary gland is a critical endocrine organ composed of at least five differentiated cell types and responsible for the secretion of thyroid-stimulating hormone (TSH), growth hormone (GH), prolactin (PRL), adrenocorticotropin (ACTH), follicle-stimulating hormone (FSH) and luteinising hormone (LH) (Kerr et al 2008; de Moraes et al 2012). Abnormal development or function of the anterior pituitary gland leads to pituitary hormone deficiency either in an isolated or combined form. Combined pituitary hormone deficiency (CPHD) is characterised by a lack of growth hormone (GH) and at least one additional pituitary. The genetics of CPHD involves at least 30 genes required in the anterior pituitary development, differentiation, and maintenance (Fang et al 2016; Castinetti et al 2016), including well-established transcription factor genes PROP1 (Wu et al 1998), POU1F1 (Tatsumi et al 1992), HESX1 (Dattani et al 1998), LHX3 (Netchine et al 2000), and LHX4 (Machinis et al 2001). A recent genotype screening of the known CPHD genes in ~ 1200 patients revealed only 7.3% and 29.5% discovery rates in sporadic and familial cases, respectively (Jullien et al 2020). The molecular aetiology remains unexplained in most patients despite the accelerating speed of gene discoveries facilitated by high throughput sequencing. Further research is warranted to improve early diagnostics and care since hormone deficiency at birth can result in hypoglycemia and death

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