Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism.
BACKGROUND
Several genetic defects are associated with permanent congenital hypothyroidism. Immunologic, environmental, and iatrogenic (but not genetic) factors are known to induce transient congenital hypothyroidism, which spontaneously resolves within the first months of life. We hypothesized that molecular defects in the thyroid oxidase system, which is composed of at least two proteins, might be involved in the pathogenesis of permanent or transient congenital hypothyroidism in babies with defects in iodide organification, for which the oxidase system is required.


METHODS
Nine patients were recruited who had idiopathic congenital hypothyroidism (one with permanent and eight with transient hypothyroidism) and an iodide-organification defect and who had been identified by the screening program for congenital hypothyroidism. The DNA of the patients and their relatives was analyzed for mutations in the genes for thyroid oxidase 1 (THOX1 ) and 2 (THOX2 ).


RESULTS
The one patient with permanent and severe thyroid hormone deficiency and a complete iodide-organification defect had a homozygous nonsense mutation in the THOX2 gene that eliminates all functional domains of the protein. Three of the eight patients with mild transient congenital hypothyroidism and a partial iodide-organification defect had heterozygous mutations in the THOX2 gene that prematurely truncate the protein, thus abolishing its functional domains.


CONCLUSIONS
Biallelic inactivating mutations in the THOX2 gene result in complete disruption of thyroid-hormone synthesis and are associated with severe and permanent congenital hypothyroidism. Monoallelic mutations are associated with milder, transient hypothyroidism caused by insufficient thyroidal production of hydrogen peroxide, which prevents the synthesis of sufficient quantities of thyroid hormones to meet the large requirement for thyroid hormones at the beginning of life.
Moreno
José C
JC
Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam. j.c.moreno@amc.uva.nl
Bikker
Hennie
H
Kempers
Marlies J E
MJ
van Trotsenburg
A S Paul
AS
Baas
Frank
F
de Vijlder
Jan J M
JJ
Vulsma
Thomas
T
Ris-Stalpers
C
C
D003409:Congenital Hypothyroidism; D004252:DNA Mutational Analysis; D000074623:Dual Oxidases; D005260:Female; D005420:Flavoproteins / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007037:Hypothyroidism / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D019255:NADPH Oxidases; D010375:Pedigree; D013963:Thyroid Hormones / Q000096:biosynthesis / Q000097:blood
D005420:Flavoproteins; D013963:Thyroid Hormones; D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431513:DUOX1 protein, human; C431515:DUOX2 protein, human