Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism
Hakan Cangul, Xiao-Hui Liao, Erik Schoenmakers, Jukka Kero, Sharon Barone, Panudda Srichomkwun, Hideyuki Iwayama, Eva G. Serra, Halil Saglam, Erdal Eren, Omer Tarim, Adeline K. Nicholas, Ilona Zvetkova, Carl A. Anderson, Fiona E. Karet Frankl, Kristien Boelaert, Marja Ojaniemi, Jarmo Jääskeläinen, Konrad Patyra, Christoffer Löf, E. Dillwyn Williams, UK10K Consortium, Manoocher Soleimani, Timothy Barrett, Eamonn R. Maher, V. Krishna Chatterjee, Samuel Refetoff, Nadia Schoenmakers
Hakan Cangul, Xiao-Hui Liao, Erik Schoenmakers, Jukka Kero, Sharon Barone, Panudda Srichomkwun, Hideyuki Iwayama, Eva G. Serra, Halil Saglam, Erdal Eren, Omer Tarim, Adeline K. Nicholas, Ilona Zvetkova, Carl A. Anderson, Fiona E. Karet Frankl, Kristien Boelaert, Marja Ojaniemi, Jarmo Jääskeläinen, Konrad Patyra, Christoffer Löf, E. Dillwyn Williams, UK10K Consortium, Manoocher Soleimani, Timothy Barrett, Eamonn R. Maher, V. Krishna Chatterjee, Samuel Refetoff, Nadia Schoenmakers
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Research Article Endocrinology Genetics

Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism

Abstract

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

Authors

Hakan Cangul, Xiao-Hui Liao, Erik Schoenmakers, Jukka Kero, Sharon Barone, Panudda Srichomkwun, Hideyuki Iwayama, Eva G. Serra, Halil Saglam, Erdal Eren, Omer Tarim, Adeline K. Nicholas, Ilona Zvetkova, Carl A. Anderson, Fiona E. Karet Frankl, Kristien Boelaert, Marja Ojaniemi, Jarmo Jääskeläinen, Konrad Patyra, Christoffer Löf, E. Dillwyn Williams, UK10K Consortium, Manoocher Soleimani, Timothy Barrett, Eamonn R. Maher, V. Krishna Chatterjee, Samuel Refetoff, Nadia Schoenmakers

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Figure 2

Clinical genotype and phenotype data for kindreds harboring SLC26A7 mutations, and functional characterization of wild-type and mutant SLC26A7.

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Clinical genotype and phenotype data for kindreds harboring SLC26A7 muta...
(A) Pedigrees of 6 kindreds illustrating cases with congenital hypothyroidism (CH) and unaffected relatives for whom genetic data were available. Thyroid hormone measurements refer to venous measurements made at diagnosis of CH or following genetic evaluation. Reference ranges: AII.i, iii, iv, v thyroid-stimulating hormone (TSH) 0.9–3.5 mU/l, free thyroxine (FT4) 1.1–1.8 ng/dl; AII.ii TSH 0.6–4.8 mU/l, FT4 0.76–1.5 ng/dl; AII.vi. vii, viii, ix TSH 0.4–3.5 mU/l, FT4 0.83–1.69 ng/dl; BII.i TSH 0.7–5.3 mU/l, FT4 1.1–1.8 ng/dl; CII.i TSH 0.6–4.8 mU/l, FT4 0.8–1.5 ng/dl; CII.ii TSH 0.4–3.5 mU/l, FT4 0.8–1.9 ng/dl; DII.i, ii, EII.i, ii, FII.i, ii TSH 0.35–40 mU/l, FT4 0.7–1.5 ng/dl. Double horizontal lines indicate consanguinity. FT4: multiply by 12.87 to convert to pmol/l. (B) Quantitative RT-PCR analysis of SLC26A7 mRNA expression in a human tissue library relative to cyclophilin; horizontal bars denote mean and vertical bars standard error of the mean. (C) Homology modeling predicting the protein consequences of the SLC26A7 p.F631Lfs*8 mutation. The deleted protein region is shown in red. (D) HEK293 cells transfected with GFP-tagged wild-type and F631Lfs*8 SLC26A7 demonstrate localization of wild-type protein to the plasma membrane, whereas the mutant remains intracellular (total original magnification, ×63). (E) Box-and-whisker plots for time-dependent iodide efflux from HEK293 cells cotransfected with NIS and pCDNA (white), pendrin (gray), or SLC26A7 (stippled black); n = 5 experiments. Boxes extend from the 25th to 75th percentiles, the horizontal line represents the median, and the vertical bars represent the minimum and maximum values.