TY - JOUR

T1 - Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome

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

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2018

Y1 - 2018

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

VL - 102

SP - 249

EP - 265

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -