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

JCI Insight. 2018 Oct 18;3(20):e99631. doi: 10.1172/jci.insight.99631.

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.

Keywords: Endocrinology; Genetics; Molecular genetics; Monogenic diseases; Thyroid disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antiporters / genetics*
  • Child
  • Child, Preschool
  • Codon, Nonsense
  • Congenital Hypothyroidism / diagnosis
  • Congenital Hypothyroidism / genetics*
  • DNA Mutational Analysis
  • Female
  • Goiter / congenital
  • Goiter / diagnosis
  • Goiter / genetics*
  • HEK293 Cells
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Pedigree
  • Sulfate Transporters / genetics*
  • Thyroid Gland / pathology
  • Whole Exome Sequencing

Substances

  • Antiporters
  • Codon, Nonsense
  • SLC26A7 protein, human
  • Slc26a4 protein, mouse
  • Sulfate Transporters