Congenital hypothyroidism due to mutations in the sodium/iodide symporter -: Identification of a nonsense mutation producing a downstream cryptic 3′ splice site

被引:92
作者
Pohlenz, J
Rosenthal, IM
Weiss, RE
Jhiang, SM
Burant, C
Refetoff, S
机构
[1] Univ Chicago, Dept Med, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA
[3] Univ Chicago, Joseph P Kennedy Jr Mental Retardat Res Ctr, Chicago, IL 60637 USA
[4] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA
[5] Ohio State Univ, Dept Physiol, Columbus, OH 43210 USA
关键词
frameshift; genetics; thyroid; iodide transport; allele-specific amplification;
D O I
10.1172/JCI1504
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 far 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.
引用
收藏
页码:1028 / 1035
页数:8
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