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 3

Characterization of the thyroid phenotype in Slc26a7-null mice and evaluation of murine thyroidal Slc26a7 expression.

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Characterization of the thyroid phenotype in Slc26a7-null mice and evalu...
(A) Box-and-whisker plots for log10TSH, T4, and T3 measurements in male wild-type (WT, white), and Slc26a7-null mice (KO, stippled black) at 14, 60, and 90 days of age; n = 6–12 mice of each genotype. Boxes extend from the 25th to 75th percentiles, the horizontal line represents the median, and the vertical bars represent the minimum and maximum values. P values were calculated using an unpaired 2-tailed Student’s t test. ***P < 0.0005. (B) Quantitative RT-PCR analysis of Slc26a7 mRNA expression in a murine tissue library relative to cyclophilin. Horizontal bars represent the mean and error bars represent the standard error of the mean. (C) Photographic representation of the thyroid gland in a male wild-type and Slc26a7-null mouse age 90 days, demonstrating goiter in the Slc26a7-null mouse. Box-and-whisker plots below quantify mean thyroid weight/body weight in 5 WT (white), 18 heterozygous (Het, gray), and 8 Slc26a7-null male mice (KO, stippled black) at P14. P values were calculated using 1-way ANOVA with the Newman-Keuls multiple-comparisons test. **P < 0.005, ***P < 0.0005. (D) Hematoxylin and eosin–stained thyroid sections from a male Slc26a7-null (KO) mouse compared with a heterozygous littermate (Het) as control age 60 days. Images are representative of sections reviewed from 3 separate goitrous mice and demonstrate enlarged, colloid-filled follicles with normal-tall follicular cells. Scale bars: 500 μm (top left) and 100 μm. (E) Representative thyroid sections from 2 different Slc26a7-FLAG male mice and a wild-type mouse age 75 days, stained with anti-FLAG antibody or preimmune serum (control). Arrows denote intracellular and basolateral localization of SLC26A7. Scale bars: 10 μm. NS, not significant.