Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site.
Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site.
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由于钠/碘同向转运蛋白突变而导致的先天性甲状腺功能减退症。
DOI：
10.1172/jci1504
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Refetoff,S
中科院分区：
文献类型：
--
作者：
Pohlenz,J;Rosenthal,IM;Weiss,RE;Jhiang,SM;Burant,C;Refetoff,S
一个12岁的甲状腺功能减退的女孩在出生时被诊断为甲状腺功能不全，因为她的甲状腺不能可视化同位素扫描。由于促甲状腺激素抑制不完全，甲状腺放射性碘摄取<1%，唾液与血浆比值低至2.5，提示碘（I-）转运缺陷，导致甲状腺肿的发展。从她的甲状腺中分离的mRNA注入爪蟾卵母细胞未能增加I-转运。测序结果表明，该基因第6外显子第1146位核苷酸（nt）发生了C → G的颠换，导致第267位Gln（CAG）→ Glu（GAG）的突变。当在COS-7细胞中表达时，这种错义突变产生具有不可检测的I-转运活性的NIS。虽然只有这种错义突变被确定在甲状腺和淋巴细胞的cDNA，基因分型显示，先证者和她的未受影响的兄弟和父亲是杂合子的这种突变。然而，用对野生型nt 1146特异的引物扩增cDNA得到缺少67个nt的序列。基因组DNA显示1940 nt的C到G颠换，产生终止密码子以及外显子13中的新的下游隐蔽3'剪接受体位点，其负责67 nt缺失、移码和提前终止，预测NIS缺少129个羧基末端氨基酸。这种突变遗传自母亲，并存在于未受影响的妹妹中。因此，尽管先证者是复合杂合子，但由于一个突变等位基因的表达非常低（< 2.5%），她在功能上是NIS的半合子，没有可检测的生物活性。
A 12-yr-old hypothyroid girl was diagnosed at birth as athyreotic because her thyroid gland could not be visualized by isotope scanning. Goiter development due to incomplete thyrotropin suppression, a thyroidal radioiodide uptake of < 1%, and a low saliva to plasma ratio of 2.5 suggested iodide (I-) transport defect. mRNA isolated from her thyroid gland and injected into Xenopus oocytes failed to increase I- transport. Sequencing of the entire Na+/I- symporter (NIS) cDNA revealed a C to G transversion of nucleotide (nt) 1146 in exon 6, resulting in a Gln 267 (CAG) to Glu (GAG) substitution. This missense mutation produces an NIS with undetectable I- transport activity when expressed in COS-7 cells. Although only this missense mutation was identified in thyroid and lymphocyte cDNA, genotyping revealed that the proposita and her unaffected brother and father were heterozygous for this mutation. However, amplification of cDNA with a primer specific for the wild-type nt 1146 yielded a sequence lacking 67 nt. Genomic DNA showed a C to G transversion of nt 1940, producing a stop codon as well as a new downstream cryptic 3' splice acceptor site in exon 13, responsible for the 67 nt deletion, frameshift, and premature stop predicting an NIS lacking 129 carboxy-terminal amino acids. This mutation was inherited from the mother and present in the unaffected sister. Thus, although the proposita is a compound heterozygote, because of the very low expression (< 2.5%) of one mutant allele, she is functionally hemizygous for an NIS without detectable bioactivity.