A Novel Peculiar Mutation in the Sodium/Iodide Symporter Gene in Spanish Siblings with Iodide Transport Defect

Kosugi, Shinji; Okamoto, Hiroomi; Tamada, Akira; Sánchez‐Franco, Franco

doi:10.1210/jcem.87.8.8767

Cited by 27 publications

(21 citation statements)

References 13 publications

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“…The resulting impairment in I − uptake in the thyroid leads to congenital hypothyroidism, which, unless treated early in life by TH administration, causes goiter and even mental retardation. Study of the 14 ITD-causing NIS mutations identified to date (27)(28)(29)(30)(31)(32)(33)(34)(35)(36) has been instrumental in the identification of residues key for NIS transport activity (5, 16, 17, 22-25, 37, 38). For example, the analysis of T354P revealed the role in NIS function of TMS9, where this mutation is located (23).…”

Section: Significancementioning

confidence: 99%

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Ferrandino

Nicola

Sánchez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The sodium/iodide symporter (NIS) mediates active I− transport in the thyroid—the first step in thyroid hormone biosynthesis—with a 2 Na+: 1 I− stoichiometry. The two Na+ binding sites (Na1 and Na2) and the I− binding site interact allosterically: when Na+ binds to a Na+ site, the affinity of NIS for the other Na+ and for I− increases significantly. In all Na+-dependent transporters with the same fold as NIS, the side chains of two residues, S353 and T354 (NIS numbering), were identified as the Na+ ligands at Na2. To understand the cooperativity between the substrates, we investigated the coordination at the Na2 site. We determined that four other residues—S66, D191, Q194, and Q263—are also involved in Na+ coordination at this site. Experiments in whole cells demonstrated that these four residues participate in transport by NIS: mutations at these positions result in proteins that, although expressed at the plasma membrane, transport little or no I−. These residues are conserved throughout the entire SLC5 family, to which NIS belongs, suggesting that they serve a similar function in the other transporters. Our findings also suggest that the increase in affinity that each site displays when an ion binds to another site may result from changes in the dynamics of the transporter. These mechanistic insights deepen our understanding not only of NIS but also of other transporters, including many that, like NIS, are of great medical relevance.

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Section: Significancementioning

confidence: 99%

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Ferrandino

Nicola

Sánchez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…3 in Kornreich et al [1990]), RB1 (see Fig. 4 in Greger et al [1990]), and SLC5A5 (MIM] 601843 [Kosugi et al, 2002]). In these genes the inserted sequence constitutes an internal portion of the removed sequence, but in inverted orientation.…”

Section: Inversions That Involve the Partial Reinsertion Of The Removmentioning

confidence: 99%

Intrachromosomal serial replication slippage intransgives rise to diverse genomic rearrangements involving inversions

et al. 2005

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Serial replication slippage in cis (SRScis) provides a plausible explanation for many complex genomic rearrangements that underlie human genetic disease. This concept, taken together with the intra- and intermolecular strand switch models that account for mutations that arise via quasipalindrome correction, suggest that intrachromosomal SRS in trans (SRStrans) mediated by short inverted repeats may also give rise to a diverse series of complex genomic rearrangements. If this were to be so, such rearrangements would invariably generate inversions. To test this idea, we collated all informative mutations involving inversions of >or=5 bp but <1 kb by screening the Human Gene Mutation Database (HGMD; www.hgmd.org) and conducting an extensive literature search. Of the 21 resulting mutations, only two (both of which coincidentally contain untemplated additions) were found to be incompatible with the SRStrans model. Eighteen (one simple inversion, six inversions involving sequence replacement by upstream or downstream sequence, five inversions involving the partial reinsertion of removed sequence, and six inversions that occurred in a more complicated context) of the remaining 19 mutations were found to be consistent with either two steps of intrachromosomal SRStrans or a combination of replication slippage in cis plus intrachromosomal SRStrans. The remaining lesion, a 31-kb segmental duplication associated with a small inversion in the SLC3A1 gene, is explicable in terms of a modified SRS model that integrates the concept of "break-induced replication." This study therefore lends broad support to our postulate that intrachromosomal SRStrans can account for a variety of complex gene rearrangements that involve inversions.

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“…The presence of charged residues (of any polarity) other than Glu at position 267 rendered NIS inactive without affecting its expression or targeting, but substitution with neutral residues at this position was compatible with partial activity. Pohlenz et al, 1998;Kosugi et al, 1999;Kosugi et al, 2002;Levy et al, 1998c) (Fig. 1A).…”

mentioning

confidence: 95%

The Q267E mutation in the sodium/iodide symporter (NIS) causes congenital iodide transport defect (ITD) by decreasing the NIS turnover number

Vieja

Ginter

Carrasco

2004

Journal of Cell Science

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The Na+/I- symporter (NIS) is a key plasma membrane glycoprotein that mediates active iodide (I-) transport in the thyroid and other tissues. Since isolation of the cDNA encoding NIS (G. Dai, O. Levy, and N. Carrasco (1996) Nature 379, 458-460), ten mutations in NIS have been identified as causes of congenital iodide transport defect (ITD). Two of these mutations (T354P and G395R) have been thoroughly characterized at the molecular level. Both mutant NIS proteins are inactive but normally expressed and correctly targeted to the plasma membrane. The hydroxyl group at the β-carbon of residue 354 is essential for NIS function, whereas the presence of a charged or large side-chain at position 395 interferes with NIS function. We report the extensive molecular analysis of the Q267E mutation in COS-7 cells transfected with rat or human Q267E NIS cDNA constructs. We used site-directed mutagenesis to engineer various residue substitutions into position 267. In contrast to previous suggestions that Q267E NIS was inactive, possibly because of a trafficking defect, we conclusively show that Q267E NIS is modestly active and properly targeted to the plasma membrane. Q267E NIS exhibited lower Vmax values for I- than wild-type NIS, suggesting that the decreased level of activity of Q267E NIS is due to a lower catalytic rate. That Q267E NIS retains even partial activity sets this ITD-causing mutant apart from T354P and G395R NIS. The presence of charged residues (of any polarity) other than Glu at position 267 rendered NIS inactive without affecting its expression or targeting, but substitution with neutral residues at this position was compatible with partial activity.

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A Novel Peculiar Mutation in the Sodium/Iodide Symporter Gene in Spanish Siblings with Iodide Transport Defect

Cited by 27 publications

References 13 publications

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Intrachromosomal serial replication slippage intransgives rise to diverse genomic rearrangements involving inversions

The Q267E mutation in the sodium/iodide symporter (NIS) causes congenital iodide transport defect (ITD) by decreasing the NIS turnover number

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A Novel Peculiar Mutation in the Sodium/Iodide Symporter Gene in Spanish Siblings with Iodide Transport Defect

Cited by 27 publications

References 13 publications

Na + coordination at the Na2 site of the Na + /I − symporter

Na + coordination at the Na2 site of the Na + /I − symporter

Intrachromosomal serial replication slippage intransgives rise to diverse genomic rearrangements involving inversions

The Q267E mutation in the sodium/iodide symporter (NIS) causes congenital iodide transport defect (ITD) by decreasing the NIS turnover number

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Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter

Na ⁺ coordination at the Na2 site of the Na ⁺ /I ⁻ symporter