Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2
Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2
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由影响 DUOX2 的 NADPH 氧化酶结构域的复合杂合突变引起的暂时性先天性甲状腺功能减退症
DOI：
10.1515/jpem-2014-0479
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发表时间：
2016
影响因子：
1.4
通讯作者：
M. Satoh
中科院分区：
文献类型：
--
作者：
Atsuko Yoshizawa;K. Abe;Sayaka Ogikubo;S. Narumi;T. Hasegawa;M. Satoh
摘要在此，我们描述了三例双氧化酶2（DUOX 2）的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）-氧化酶（NOX）结构域功能缺失突变，沿着甲状腺过氧化物酶（TPO）的错义突变，导致短暂性先天性甲状腺功能减退症（CH）。三个日本男孩与非血缘的父母被诊断为CH在他们的新生儿筛查。所有患者均表现为中度至重度新生儿甲状腺功能减退症，在重新评估甲状腺功能后诊断为一过性CH。两个兄弟姐妹为p复合杂合子。[R1110 Q]+[Y1180 X]，其中1例为p. [R361 L]在TPO中。第3例患者为p复合杂合子。[L1160 del]+[R1334 W]为DUOX 2杂合子; [P883 S]在TPO中。这是首次报道影响DUOX 2基因的从头L1160 del突变以及DUOX 2中的新型突变Y1180 X和TPO中的R361 L。发现R1110 Q和L1160 del减少H2 O2产生（5%-9%，p<0.01），而引入提前终止密码子的Y1180 X没有赋予可检测的H2 O2产生（-0.7%至0.6%，p<0.01）。此外，可能影响电子传递的错义突变R1334 W导致体外H2 O2产生减少（24%± 0.9%，p<0.01），并且R1110 Q和R1334 W导致蛋白表达减少。Y1180 X以120 kDa的截短形式被检测到，而L1160 del表达得以维持。此外，R361 L，一种新的TPO错义突变，引起过氧化物酶活性的部分降低（20.6%± 0.8%，p=0.01），而P883 S，一种错义变体，增加了它（133.7%± 2.8%，p=0.02）。在R361 L和P883 S的情况下，蛋白质表达水平得以维持。总之，我们提供了临床和体外实验证明，不同的功能缺陷和表型异质性，在同一甲状腺增生途径。
Abstract Here, we describe three cases of loss-of-function mutations in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase (NOX) domain of dual oxidase 2 (DUOX2) occurring along with concurrent missense mutations in thyroid peroxidase (TPO), leading to transient congenital hypothyroidism (CH). Three Japanese boys with nonconsanguineous parents were diagnosed with CH during their neonatal screenings. All patients presented with moderate-to-severe neonatal hypothyroidism and were diagnosed with transient CH after re-evaluation of thyroid function. Two siblings were compound heterozygous for p.[R1110Q]+[Y1180X] in DUOX2; one of them was also heterozygous for p.[R361L] in TPO. The third patient was compound heterozygous for p.[L1160del]+[R1334W] in DUOX2 and heterozygous for p.[P883S] in TPO. This is the first report of a de novo L1160del mutation affecting the DUOX2 gene and of the novel mutations Y1180X in DUOX2 and R361L in TPO. R1110Q and L1160del were found to reduce H2O2 production (5%–9%, p<0.01), while Y1180X, which introduces a premature stop codon, did not confer detectable H2O2 production (–0.7%±0.6%, p<0.01). Moreover, R1334W, a missense mutation possibly affecting electron transfer, led to reduced H2O2 production (24%±0.9%, p<0.01) in vitro, and R1110Q and R1334W resulted in reduced protein expression. Y1180X was detected in a 120 kDa truncated form, whereas L1160del expression was maintained. Further, R361L, a novel missense mutation in TPO, caused partial reduction in peroxidase activity (20.6%±0.8%, p=0.01), whereas P883S, a missense variant, increased it (133.7%±2.8%, p=0.02). The protein expression levels in the case of R361L and P883S were maintained. In conclusion, we provide clinical and in vitro demonstrations of different functional defects and phenotypic heterogeneity in the same thyroid hormonogenesis pathway.
影响因子：
5.8
作者：
Sriphrapradang, Chutintorn;Tenenbaum-Rakover, Yardena;Refetoff, Samuel
通讯作者：
Refetoff, Samuel