Topic: Mutations in congenital hypothyroidism
Title -Congenital hypothyroidism, dwarfism and hearing impairment caused by a missense mutation in the mouse dual oxidase 2 gene, Duox 2.
Authors: Johnson KR, Marden CC, Ward-Bailey P, Gagnon LH, Bronson RT, & Donahue LR
Reference: Molecular Endocrinology (first published ahead of print April 17, 2007)
The mouse dual oxidases Duox1 and Duox2 genes, like the orthologous human DUOX1 and DUOX2 genes [also known as thyroid oxidases ( THOX1 and THOX2 )], are highly expressed in the thyroid gland and encode cell surface glycoproteins that function as NADPH oxidases. They generate hydrogen peroxide (H 2 0 2 ) at the apical membrane of thyroid follicular cells, which is required by thyroid peroxidase (TPO) for the incorporation of iodine into thyroglobulin (TG), an essential step (iodide organification) in the synthesis of thyroid hormone. Loss-of-function mutations of DUOX2 , in humans with congenital hypothyroidism have established its essential role in thyroid hormonogenesis.
Identify the cause of hypothyroidism in a newly recognized spontaneous mutation in a mouse that occurred at The Jackson Laboratory. Mutant mice were congenitally hypothyroid with an associated dwarfing and hearing impairment.
Genetic mapping of the new spontaneous mouse mutation. A linkage intercross was used to map the mutation. F1 hybrids produced from mating host females carrying transplanted mutant ovaries with CAST/EiJ males were intercrossed and 98 mutant F2 progeny (196 meioses) were analyzed for segregation of chromosomal markers and their associations with the dwarf phenotype.
Identification of a missense mutation in Chromosome 2, with a C to T base pair change in exon 16 of the Duox2 gene. The mutation changes a highly conserved valine to glycine at the amino-acid position 674 (V674G) and was named -thyroid dyshormonogenesis- (symbol thyd) to signify a defect in thyroid hormone synthesis. Serum thyroxine (T4) in homozygotes was about 10-fold lower than that in controls and was accompanied by a more than 100-fold increase in thyroid stimulating hormone (TSH). The weight of adult mutant mice is approximately half that of the littermate controls and serum insulin-like growth factor 1 (IGF-I) was reduced. The cochleae of mutant mice exhibited 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 were on average 50-60 decibels (dB) above those of controls.
The Duox2 thyd mutant mice provide a new genetic model for studying the underlying molecular mechanisms and pathophysiology of congenital hypothyroidism.
Duox2 thyd mutant mice will be valuable for the investigation of the underlying molecular mechanisms and pathophysiologies of thyroid hormone (TH) synthesis and for discerning the specific functions of DUOX2 and DUOX1 in the thyroid gland and in other tissues where they are believed to play important roles in the regulated production of hydrogen peroxide. These animals will also serve as invaluable controls for mice deficient in DuoxA2 that will be generated in the future. The latter will be used in studies aimed to determine the precise function of the recently identified DUOX1 and 2 maturation factors or DUOX activators (DUOXA), transmembrane proteins that are absolutely required for the maturation and enzymatic activation of DUOX1 and DUOX2.
( Summary and commentary prepared by Sam Refetoff )
Present summary & commentary are related to Chapters N- 2 & 16 of the TDM