Rivolta Carina M, Louis-Tisserand Mariana, Varela Viviana, Gruñeiro-Papendieck Laura, Chiesa Ana, González-Sarmiento Rogelio, Targovnik Héctor M
Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina.
Clin Endocrinol (Oxf). 2007 Aug;67(2):238-46. doi: 10.1111/j.1365-2265.2007.02869.x. Epub 2007 Jun 4.
Iodide organification defects are frequently but not always associated with mutations in the thyroid peroxidase (TPO) gene and characterized by a positive perchlorate discharge test. These mutations phenotypically produce a congenital goitrous hypothyroidism, with an autosomal recessive mode of inheritance.
In the present study we extended our initial molecular studies in six unrelated patients heterozygous for the TPO mutations, in order to identify the second mutation in this autosomal recessive disease.
The promoter and the complete coding regions of the human TPO and DUOXA2 genes, along with the flanking regions of each intron were analysed by direct DNA sequencing.
Four different inactivating TPO mutations were identified in two patients: two novel mutations (c.215delA [p.Q72fsX86] and c.1159G-->A [p.G387R]) and two previously reported (c.387delC [p.N129fsX208] and c.2422T-->C [p.C808R]), confirming the inheritance of two different compound heterozygous mutations, c.215delA/c.2422T-->C and c.387delC/c.1159G-->A. The remaining four patients did not show additional inactivating mutations in the TPO gene and all had only the wild type sequencing in the DUOXA2 gene.
We have reported two patients with iodide organification defect caused by two compound heterozygous mutations, c.215delA/c.2422T-->C [p.Q72fsX86/p.C808R] and c.387delC/c.1159G-->A [p.N129fsX208/p.G387R], in the TPO gene and four patients with monoallelic TPO defect. Identification of the molecular basis of this disorder might be helpful for understanding the pathophysiology of congenital hypothyroidism.
碘有机化缺陷常与甲状腺过氧化物酶（TPO）基因突变相关，但并非总是如此，其特征为高氯酸盐释放试验阳性。这些突变在表型上导致先天性甲状腺肿性甲状腺功能减退，呈常染色体隐性遗传模式。
在本研究中，我们对6名TPO突变杂合的无关患者进行了进一步的分子研究，以确定这种常染色体隐性疾病中的第二个突变。
通过直接DNA测序分析人TPO和DUOXA2基因的启动子、完整编码区以及每个内含子的侧翼区域。
在两名患者中鉴定出四种不同的TPO失活突变：两种新突变（c.215delA [p.Q72fsX86]和c.1159G→A [p.G387R]）和两种先前报道的突变（c.387delC [p.N129fsX208]和c.2422T→C [p.C808R]），证实了两种不同的复合杂合突变c.215delA/c.2422T→C和c.387delC/c.1159G→A的遗传。其余四名患者在TPO基因中未显示额外的失活突变，且在DUOXA2基因中均只有野生型测序结果。
我们报道了两名由TPO基因中的两种复合杂合突变c.215delA/c.2422T→C [p.Q72fsX86/p.C808R]和c.387delC/c.1159G→A [p.N129fsX208/p.G387R]引起碘有机化缺陷的患者，以及四名单等位基因TPO缺陷患者。确定这种疾病的分子基础可能有助于理解先天性甲状腺功能减退的病理生理学。
