A Novel Homozygous Mutation in the Solute Carrier Family 26 Member 7 Gene Causes Thyroid Dyshormonogenesis in a Girl with Congenital Hypothyroidism

Introduction

Approximately 15–20% of congenital hypothyroidisms are due to thyroid dyshormonogenesis, in which the thyroid is properly located but biosynthesis of thyroid hormones is impaired. Mutations in only a few candidate genes (TG, TPO, DUOX2, DUOXA2, SLC26A4, SLC5A5, and IYD) for this condition have been identified (1). Recently, solute carrier family 26 member 7 (SLC26A7) was reported to function as a new iodide transporter in the thyroid, playing a hitherto unrecognized role in the process of thyroid hormone biosynthesis (2,3). We, therefore, investigated a girl with thyroid dyshormonogenesis for SLC26A7 sequence alterations who had no mutation in the known candidate genes.

Materials and Methods

Results

Sequencing analysis revealed a novel homozygous deletion (c.1432_1433delGT, p.V478KfsX11) in exon 14 of the SLC26A7 gene, which leads to a frameshift and a premature stop at position 489. Both parents and the brother were heterozygous carriers of this mutation (Fig. 1A). In silico analysis showed that c.1432_1433delGT, p.V478KfsX11 is not a common polymorphism and, therefore, pathogenic.

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FIG. 1.

(A) Electropherograms of the Sanger sequencing results of a wild type control (upper panel), the patient (second panel), and a heterozygous sequence (third panel) that is representative of all heterozygous family members (parents and brother). The wild type amino acid sequences are indicated with a black letter and the altered amino acid sequences in red above the coding sequence. The deletion of the coding sequence is highlighted in the wild type since it is not visible in the homozygous mutant electropherogram. The mutation involves only one allele in the heterozygous sequence resulting in the shift of the allele with the deletion and hence overlapping chromatograms. (B) Comparison of wild type and mutant SLC26A7 protein structures. Both proteins have 12 putative transmembrane domain segments. The mutation, which is indicated in red, leads to a truncated protein lacking the C-terminus including the essential sulphate transporter and anti-sigma factor antagonist domain. Color images are available online.

Discussion

We describe a rare case of thyroid dyshormonogenesis due to a novel homozygous mutation in the SLC26A7 gene. So far, only six SLC26A7 mutations have been identified (2 –5) that are nucleotide substitutions, deletions, or insertions leading to a truncated protein. We found two base pair deletions causing a frameshift and also a premature termination codon. The resulting transcript, if expressed at all, is predicted to translate into a severely truncated protein (Fig. 1B), which is not likely to be functional. Even though the exact location and function of SLC26A7 remain controversial (2,3), based on the studies of Ishii et al. it can be predicted that the truncation causes loss of the essential sulphate transporter and anti-sigma factor antagonist domain, which presumably leads to abnormal processing of the protein (3).

Interestingly, the phenotype of patients harboring SLC26A7 mutations varies. The majority of patients are diagnosed by neonatal screening and present with congenital hypothyroidism, goiter, and elevated serum thyroglobulin levels (2 –5), but hypothyroidism may also become evident later in life (3). Awareness of this condition will help to identify more patients harboring SLC26A7 mutations and eventually initiate further studies to elucidate the precise location and function of this protein.