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Am J Hum Genet. 2018 Feb 1;102(2):249-265. doi: 10.1016/j.ajhg.2017.12.017.

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

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CIC bioGUNE, Bizkaia Technology Park, Building 801-A, 48160 Derio, Bizkaia, Spain.
Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b, 2200 Copenhagen, Denmark.
Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
SYNLAB Center for Human Genetics Freiburg, Heinrich-von-Stephan-Straße 5, 79100 Freiburg, Germany.
Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK.
Ipswich Hospital NHS Trust, Heath Road, Ipswich IP4 5PD, Suffolk, UK.
Saint Louis University School of Medicine, 1100 South Grand Boulevard, St. Louis, MO 63104, USA; VA St. Louis Health Care System, St. Louis, MO 63106, USA.
CIC bioGUNE, Bizkaia Technology Park, Building 801-A, 48160 Derio, Bizkaia, Spain. Electronic address:
CIC bioGUNE, Bizkaia Technology Park, Building 801-A, 48160 Derio, Bizkaia, Spain. Electronic address:


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.


BioID; SALL1; Townes-Brocks syndrome; primary cilia; rare disease; spalt

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