Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome
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 mut...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Published: |
Cell Press
2018
|
| _version_ | 1826278854253084672 |
|---|---|
| author | Bozal-Basterra, L Martín-Ruíz, M Pirone, L Liang, Y Otti Sigurdsson, J Gonzalez-Santamarta, M Giordano, I Gabicagogeascoa, E de Luca, A Rodríguez, J Wilkie, A Kohlhase, J Eastwood, D Yale, C Olsen, J Rauchman, M Anderson, K Sutherland, J Barrio, R |
| author_facet | Bozal-Basterra, L Martín-Ruíz, M Pirone, L Liang, Y Otti Sigurdsson, J Gonzalez-Santamarta, M Giordano, I Gabicagogeascoa, E de Luca, A Rodríguez, J Wilkie, A Kohlhase, J Eastwood, D Yale, C Olsen, J Rauchman, M Anderson, K Sutherland, J Barrio, R |
| author_sort | Bozal-Basterra, L |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:50:10Z |
| format | Journal article |
| id | oxford-uuid:7253d3b3-7b6e-40e1-8e6d-6d5c016430b6 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T23:50:10Z |
| publishDate | 2018 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:7253d3b3-7b6e-40e1-8e6d-6d5c016430b62022-03-26T19:49:24ZTruncated SALL1 impedes primary cilia function in Townes-Brocks SyndromeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7253d3b3-7b6e-40e1-8e6d-6d5c016430b6Symplectic Elements at OxfordCell Press2018Bozal-Basterra, LMartín-Ruíz, MPirone, LLiang, YOtti Sigurdsson, JGonzalez-Santamarta, MGiordano, IGabicagogeascoa, Ede Luca, ARodríguez, JWilkie, AKohlhase, JEastwood, DYale, COlsen, JRauchman, MAnderson, KSutherland, JBarrio, RTownes-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. |
| spellingShingle | Bozal-Basterra, L Martín-Ruíz, M Pirone, L Liang, Y Otti Sigurdsson, J Gonzalez-Santamarta, M Giordano, I Gabicagogeascoa, E de Luca, A Rodríguez, J Wilkie, A Kohlhase, J Eastwood, D Yale, C Olsen, J Rauchman, M Anderson, K Sutherland, J Barrio, R Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome |
| title | Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome |
| title_full | Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome |
| title_fullStr | Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome |
| title_full_unstemmed | Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome |
| title_short | Truncated SALL1 impedes primary cilia function in Townes-Brocks Syndrome |
| title_sort | truncated sall1 impedes primary cilia function in townes brocks syndrome |
| work_keys_str_mv | AT bozalbasterral truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT martinruizm truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT pironel truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT liangy truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT ottisigurdssonj truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT gonzalezsantamartam truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT giordanoi truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT gabicagogeascoae truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT delucaa truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT rodriguezj truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT wilkiea truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT kohlhasej truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT eastwoodd truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT yalec truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT olsenj truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT rauchmanm truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT andersonk truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT sutherlandj truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome AT barrior truncatedsall1impedesprimaryciliafunctionintownesbrockssyndrome |