TG Nonsense Variant in Dwarf Rottweiler Dogs.

Area of Science:

• Canine genetics
• Endocrinology
• Veterinary medicine

Background:

• A novel dwarfism syndrome was observed in Rottweiler dogs, presenting with distinct physical and developmental abnormalities.
• Affected puppies exhibited reduced growth, limb deformities, tail shortening, thickened skin, developmental delays, pain, and non-goitrous hypothyroidism.
• Thyroid gland histology revealed severe chronic atrophy and loss of functional tissue, indicating a significant endocrine disruption.

Purpose of the Study:

• To characterize the clinical and pathological features of this inherited dwarfism syndrome in Rottweilers.
• To identify the genetic cause of the observed syndrome.
• To develop a genetic test for carrier detection and breeding management.

Main Methods:

• Clinical and pathological examinations of affected Rottweilers.
• Autosomal recessive inheritance pattern suggested by pedigree analysis.
• Whole genome sequencing and variant filtering against a large control cohort.
• Genotyping of affected dogs, controls, and obligate carriers to confirm genotype-phenotype association.

Main Results:

• Whole genome sequencing identified a homozygous nonsense variant (NM_001048104.1:c.3694C>T) in the thyroglobulin (TG) gene in affected dogs.
• This variant is predicted to cause a premature stop codon, truncating 55% of the TG protein (NP_001041569.1:p.(Arg1232*)).
• Genotyping confirmed a strong genotype-phenotype correlation, with a 5.4% carrier frequency in the control population.

Conclusions:

• The identified TG gene variant is the causal genetic defect responsible for the inherited dwarfism syndrome in Rottweilers.
• Thyroglobulin deficiency leads to hypothyroidism and dwarfism, consistent with findings in human and other animal models.
• The genetic test allows for informed breeding decisions to prevent the occurrence of this syndrome in the breed.