Spalt-like (SALL) Family of Transcription Factors and rare diseases

Mutations in the Spalt-like (SALL) family of zinc finger transcription factors are associated with various hereditary syndromes, including Townes-Brocks Syndrome (TBS) and Okihiro (Duane-Radial Ray) Syndromes. These syndromes are considered rare diseases and are characterized by symptoms such as hearing loss, renal and limb malformations, among others. We have shown that TBS patient-derived cells have longer and more frequent primary cilia than control cells, leading to errors in the Sonic hedgehog signaling pathway.

Rare diseases: what are they and who do they affect?

Rare diseases are medical conditions with a prevalence of less than 1 case per 2000 inhabitants. There are estimated to be between 5,000 and 7,000 different rare diseases, and while each one may affect only a small number of individuals worldwide, collectively they impact a significant portion of the global population. It is estimated that between 6 and 8% of the world's population could be affected by one of these rare diseases, resulting in approximately 30 million Europeans suffering from various rare conditions.

In our laboratory, we focus on comprehending the underlying mechanisms of Townes-Brocks Syndrome and other diseases associated with the Ubiquitin-like family, such as Angelman Syndrome.

Spalt-like (SALL) Family of Transcription Factors and Townes-Brocks Syndrome

Our research focuses on understanding the mechanism through which truncations in SALL1 lead to Townes-Brocks Syndrome. By analyzing cells derived from affected patients, we have discovered that primary cilia are longer and more abundant in these cells compared to control cells.

*We express our heartfelt gratitude to the donors and their families who have contributed to this research*.

We study Townes-Brocks Syndrome using both human and mouse cellular models. In Drosophila, we have explored the role of Sall factors in neurodegeneration, limb formation, and nervous system development. Additionally, we have investigated the modification of these proteins by the Small ubiquitin-like modifier (SUMO) and how this modification affects their functions.

If you or a family member are affected by Townes-Brocks Syndrome, please click here.

Ubiquitin-like proteins in development and disease

Post-translational modifications (PTMs) mediated by members of the ubiquitin/ubiquitin-like (UbL) family play a vital role in cell survival and the proper functioning of organisms. These modifications involve conserved enzymatic pathways that attach UbLs to other proteins, determining the fate of the target protein. This can lead to changes in its protein-protein interactions, subcellular localization, stability, and degradation. Dysfunctions in these modifications are implicated in various diseases, including cancer, diabetes, neurodegeneration, and rare disorders.

Regulation of protein homeostasis in diseases

Townes-Brocks Syndrome is caused by mutations in SALL1 that result in a truncated protein, which disrupts cytoplasmic factors and impacts primary cilia. The truncated N-terminal fragment of SALL1 causes changes in the stability of interacting proteins, such as the leucine-zipper protein LUZP1, a negative regulator of ciliogenesis. Our ongoing research aims to study LUZP1 protein homeostasis and whether truncated SALL1 can influence its regulation..

Tools to study ubiquitin-like modifications

We are interested in exploring the role of ubiquitin/ubiquitin-like (UbL) family members during development under normal physiological conditions and their implications in disease processes. However, studying UbL modifications is particularly challenging because they are transient and occur in only a small fraction of the total protein pool. To overcome these challenges, we are actively developing a series of biotin-based strategies to investigate the modifications by UbLs and their subsequent consequences. We also employ other techniques, as TUBEs and SUBEs, and others.

Ubiquitin-related Networks

Working in cooperation with other groups makes science to advance faster and is more fun. Along the years, we participated in the following networks in the fields of proteostasis, ubiquitin-like proteins and associated processes.