Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome

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; Jesper V. Olsen; Michael Rauchman; Kathryn V Anderson; James D Sutherland; Rosa Barrio

doi:10.1016/j.ajhg.2017.12.017

Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome

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, Jesper V. Olsen, Michael Rauchman, Kathryn V Anderson, James D Sutherland, Rosa Barrio

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Abstract

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 language	English
Journal	American Journal of Human Genetics
Volume	102
Issue number	2
Pages (from-to)	249-265
Number of pages	17
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2017.12.017
Publication status	Published - 1 Feb 2018

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Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks SyndromeFinal published version, 3.45 MBLicence: CC BY-NC-ND

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Bozal-Basterra, L., Martín-Ruíz, I., Pirone, L., Liang, Y., Sigurðsson, J. O., Gonzalez-Santamarta, M., Giordano, I., Gabicagogeascoa, E., de Luca, A., Rodríguez, J. A., Wilkie, A. O. M., Kohlhase, J., Eastwood, D., Yale, C., Olsen, J. V., Rauchman, M., Anderson, K. V., Sutherland, J. D., & Barrio, R. (2018). Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome. American Journal of Human Genetics, 102(2), 249-265. https://doi.org/10.1016/j.ajhg.2017.12.017

Bozal-Basterra, L, Martín-Ruíz, I, Pirone, L, Liang, Y, Sigurðsson, JO, Gonzalez-Santamarta, M, Giordano, I, Gabicagogeascoa, E, de Luca, A, Rodríguez, JA, Wilkie, AOM, Kohlhase, J, Eastwood, D, Yale, C, Olsen, JV, Rauchman, M, Anderson, KV, Sutherland, JD & Barrio, R 2018, 'Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome', American Journal of Human Genetics, vol. 102, no. 2, pp. 249-265. https://doi.org/10.1016/j.ajhg.2017.12.017

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title = "Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome",

abstract = "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.",

author = "Laura Bozal-Basterra and Itziar Mart{\'i}n-Ru{\'i}z and Lucia Pirone and Yinwen Liang and Sigur{\dh}sson, {J{\'o}n Otti} and Maria Gonzalez-Santamarta and Immacolata Giordano and Estibaliz Gabicagogeascoa and {de Luca}, Angela and Rodr{\'i}guez, {Jose A} and Wilkie, {Andrew O M} and J{\"u}rgen Kohlhase and Deborah Eastwood and Christopher Yale and Olsen, {Jesper V.} and Michael Rauchman and Anderson, {Kathryn V} and Sutherland, {James D} and Rosa Barrio",

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AU - Bozal-Basterra, Laura

AU - Martín-Ruíz, Itziar

AU - Pirone, Lucia

AU - Liang, Yinwen

AU - Sigurðsson, Jón Otti

AU - Gonzalez-Santamarta, Maria

AU - Giordano, Immacolata

AU - Gabicagogeascoa, Estibaliz

AU - de Luca, Angela

AU - Rodríguez, Jose A

AU - Wilkie, Andrew O M

AU - Kohlhase, Jürgen

AU - Eastwood, Deborah

AU - Yale, Christopher

AU - Olsen, Jesper V.

AU - Rauchman, Michael

AU - Anderson, Kathryn V

AU - Sutherland, James D

AU - Barrio, Rosa

PY - 2018/2/1

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N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2017.12.017

DO - 10.1016/j.ajhg.2017.12.017

M3 - Journal article

C2 - 29395072

SN - 0002-9297

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SP - 249

EP - 265

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome

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