Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome

Research output: Contribution to journalJournal articleResearchpeer-review


  • Laura Bozal-Basterra
  • Itziar Martín-Ruíz
  • Lucia Pirone
  • Yinwen Liang
  • Jón Otti Sigurðsson
  • Maria Gonzalez-Santamarta
  • Immacolata Giordano
  • Estibaliz Gabicagogeascoa
  • Angela de Luca
  • Jose A Rodríguez
  • Andrew O M Wilkie
  • Jürgen Kohlhase
  • Deborah Eastwood
  • Christopher Yale
  • Olsen, Jesper Velgaard
  • Michael Rauchman
  • Kathryn V Anderson
  • James D Sutherland
  • Rosa Barrio

Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Issue number2
Pages (from-to)249-265
Number of pages17
Publication statusPublished - 2018

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