Congenital hypothyroidism, dwarfism, and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 gene, Duox2.
Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T>G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named "thyroid dyshormonogenesis" (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T(4) in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50-60 decibels (dB) above those of controls.
Johnson
Kenneth R
KR
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. ken.johnson@jax.org
Marden
Coleen C
CC
Ward-Bailey
Patricia
P
Gagnon
Leona H
LH
Bronson
Roderick T
RT
Donahue
Leah Rae
LR
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D003051:Cochlea / Q000473:pathology; D003409:Congenital Hypothyroidism / Q000097:blood / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D000074623:Dual Oxidases; D004392:Dwarfism / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005420:Flavoproteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D034381:Hearing Loss / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D019255:NADPH Oxidases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D011247:Pregnancy; D017386:Sequence Homology, Amino Acid; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood
D017931:DNA Primers; D005420:Flavoproteins; D007334:Insulin-Like Growth Factor I; D013972:Thyrotropin; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human; C519130:Duox1 protein, mouse; D013974:Thyroxine