Karthik Raj; Catherine V. Morrow; Anne Traas; Angela M. Erat; Marisa Van Hoeven; Hamutal Mazrier; Mark E. Haskins; Urs Giger
Section of Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
Congenital hypothyroidism (CH) has been reported in many species; the hereditary forms can be divided into thyroid dysmorphogenesis and dyshormonogenesis. While thyroid hypoplasia has been described in dogs and cats, the molecular basis remains unknown. In contrast, several breeds of dogs with goiterous CH, studied by Fyfe et al., were found to have deficient thyroid peroxidase (TPO) activity and disease-causing TPO gene mutations. The purpose of our study was to characterize a family of domestic shorthair cats with goiterous CH.
Clinical features included dwarfism and dullness, known as cretinism and seen with CH in all species, but also constipation and megacolon, which are unique to cats with CH. Pedigree analysis documented an autosomal recessive mode of inheritance. Affected kittens developed a goiter and had low serum thyroxine (T4) and triiodothyronine (T3) when compared to controls, but high thyroid-stimulating (TSH) hormone levels indicating thyroid dyshormonogenesis. Oral thyroid supplementation corrected the progression of clinical signs and prevented further constipation and reversed the megacolon.
The TPO enzyme activity was extremely low in hypothyroid cats when compared to that of normal cats. Genomic DNA and cDNA from affected, carrier, and normal cats were extracted and sequenced based upon primers developed from the feline genome database. A homozygous missense point mutation (c.1333G>A) in TPO, which results in an amino acid change (p.Ala445Thr), was discovered in affected cats and the mutant allele segregated within the family with goiterous CH. This is the first report of a TPO deficiency in cats. Unrelated domestic shorthair cats with goiterous CH did not have this same TPO mutation. The prevalence of this TPO mutation in the domestic cat population seems low, but CH is likely underreported in cats.
Supported in part by NIH OD 010939.