Molecular Features of SLC26A4 Common Variant p.L117F

Arnoldas Matulevičius, Emanuele Bernardinelli, Zippora Brownstein, Sebastian Roesch, Karen B. Avraham*, Silvia Dossena*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The SLC26A4 gene, which encodes the anion exchanger pendrin, is involved in determining syndromic (Pendred syndrome) and non-syndromic (DFNB4) autosomal recessive hearing loss. SLC26A4 c.349C>T, p.L117F is a relatively common allele in the Ashkenazi Jewish community, where its minor allele frequency is increased compared to other populations. Although segregation and allelic data support the pathogenicity of this variant, former functional tests showed characteristics that were indistinguishable from those of the wild-type protein. Here, we applied a triad of cell-based assays, i.e., measurement of the ion transport activity by a fluorometric method, determination of the subcellular localization by confocal microscopy, and assessment of protein expression levels, to conclusively assign or exclude the pathogenicity of SLC26A4 p.L117F. This protein variant showed a moderate, but significant, reduction in ion transport function, a partial retention in the endoplasmic reticulum, and a strong reduction in expression levels as a consequence of an accelerated degradation by the Ubiquitin Proteasome System, all supporting pathogenicity. The functional and molecular features of human pendrin p.L117F were recapitulated by the mouse ortholog, thus indicating that a mouse carrying this variant might represent a good model of Pendred syndrome/DFNB4.

Original languageEnglish
Article number5549
JournalJournal of Clinical Medicine
Issue number19
StatePublished - Oct 2022


  • DFNB4
  • Pendred syndrome
  • SLC26A4
  • functional testing
  • hearing loss
  • pendrin


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