Congenital hypothyroidism caused by new mutations in the thyroid oxidase 2 (THOX2) gene.
OBJECTIVE
Congenital primary hypothyroidism (CH) occurs in one of 4000 births and in 20% of the cases CH is due to a defect in thyroid hormonogenesis. Candidate genes were examined to determine the precise aetiology of suspected dyshormonogenesis in CH.


METHODS
The genes that code for thyroid peroxidase (TPO), pendrin (PDS), sodium iodide symporter (NIS) and thyroid oxidase 2 (THOX2) were sequenced directly from genomic DNA.


METHODS
Two girls found to have CH in the neonatal screening programme and suspected of having thyroid dyshormonogenesis were investigated to identify their molecular defect.


RESULTS
Patient A had a novel heterozygous 1 bp insertion in the THOX2 gene (ins602g). This insertion results in a frameshift that predicts a premature stop at codon 300. Analysis of cDNA, transcribed from lymphocyte RNA, showed that this mutation causes skipping of exon 5, resulting in a frameshift and a premature stop at codon 254. The euthyroid mother was also a heterozygous carrier of the mutation whereas the father was homozygous for the wild-type THOX2 gene. In patient B, compound heterozygous mutations (ins602g-->fsX300 and D506N) were identified. D506N was present in one allele of the clinically unaffected mother and in a brother, whereas the euthyroid father was heterozygous for ins602g. Sixty normal individuals did not harbour the mutations. Sequencing of the TPO, PDS and NIS genes revealed no mutations.


CONCLUSIONS
The identified THOX2 mutations, which have not been described previously, are the probable causes of CH in the patients. Mutations in the THOX2 gene should be considered as the molecular cause of CH in young patients with thyroid dyshormonogenesis.
Pfarr
Nicole
N
Children's Hospital of the Johannes Gutenberg University, Mainz, Germany.
Korsch
Eckhard
E
Kaspers
Stefan
S
Herbst
Antje
A
Stach
Armin
A
Zimmer
Claudia
C
Pohlenz
Joachim
J
D001483:Base Sequence; D003409:Congenital Hypothyroidism / Q000235:genetics*; D004252:DNA Mutational Analysis; D000074623:Dual Oxidases; D005091:Exons; D005260:Female; D005420:Flavoproteins / Q000235:genetics*; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009154:Mutation; D019255:NADPH Oxidases / Q000235:genetics*; D015997:Neonatal Screening
D005420:Flavoproteins; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431515:DUOX2 protein, human