Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism.
BACKGROUND
Dual oxidase 2 (DUOX2) is the catalytic core of the H(2)O(2) generator crucial for the iodination of thyroglobulin in thyroid hormone synthesis. DUOX2 deficiency produces congenital hypothyroidism (CH) in humans and mice. We recently cloned a novel gene, the product of which (dual oxidase maturation factor 2; DUOXA2) is required to express DUOX2 enzymatic activity.


OBJECTIVE
Our objective was to identify DUOXA2 mutations as a novel cause of CH due to dyshormonogenesis.


METHODS
Subjects included 11 CH patients with partial iodine organification defect but negative for other known genetic causes of partial iodine organification defect.


RESULTS
One Chinese patient born to nonconsanguineous parents was homozygous for a nonsense mutation (p.Y246X), producing a truncated DUOXA2 protein lacking transmembrane helix 5 and the C-terminal cytoplasmic domain. The mutant protein was inactive in reconstituting DUOX2 in vitro. Pedigree analysis demonstrated recessive inheritance, because heterozygous carriers had normal thyroid function including negative results in neonatal TSH screening. One heterozygous carrier of Y246X was identified in unrelated Chinese controls (n = 92) but not in Caucasian or Japanese controls, indicating that homozygosity for Y246X could be a frequent cause of CH in Chinese. Functional studies suggest that the DUOXA2 paralog (DUOXA1) can partially compensate DUOXA2 deficiency, consistent with the proband having a milder CH phenotype than patients with biallelic DUOX2 nonsense mutations.


CONCLUSIONS
We report the first mutation in DUOXA2, identified in a patient with CH and dyshormonogenic goiter. Results of our studies provide evidence for the critical role of DUOXA2 in thyroid hormonogenesis. Biallelic DUOXA2 mutations are a novel genetic event in permanent CH.
Laboratory of Pediatric Endocrinology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
Ilaria
I
Zamproni
Helmut
H
Grasberger
Francesca
F
Cortinovis
Maria Cristina
MC
Vigone
Giuseppe
G
Chiumello
Stefano
S
Mora
Kazumichi
K
Onigata
Laura
L
Fugazzola
Samuel
S
Refetoff
Luca
L
Persani
Giovanna
G
Weber
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D018389:Codon, Nonsense; D003409:Congenital Hypothyroidism / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D006042:Goiter / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree
D018389:Codon, Nonsense; C513411:DUOXA2 protein, human; D008565:Membrane Proteins