De novo talin-1 variant L353F connects multifaceted clinical symptoms to alterations in talin-1 function

Abstract

Focal adhesion kinase; Missense mutation; Paxillin

Kinasa d'adhesió focal; Mutació de sentit erroni; Paxil·lina

Quinasa de adhesión focal; Mutación de sentido erróneo; Paxilina

Talin-1 is a central integrin adapter protein connecting cytoplasmic domains of integrins to the cytoskeleton. These talin-1-mediated mechanical linkages are crucial for cellular functions such as cell movement and connections with other cells. Here, we report a patient carrying a missense variant, L353F, in the talin-1 head which is associated with a complex set of symptoms, including skin lesions, blood cell abnormalities, and congenital cataracts. We conducted structural and cellular characterization of this variant. Recombinant talin-1 F2F3 fragment with the corresponding mutation showed a decrease in thermal stability and decreased solubility. Reconstitution of talin-deficient cells with L353F talin-1 revealed decreased cell migration velocity, defects in wound healing capacity, and changes in recruitment of the focal adhesion complex protein paxillin. We also observed decreased levels of activated integrin in cells expressing the talin-1 variant, while integrin-binding affinity was preserved as determined biochemically. These observations suggest that changes in integrin adhesion complex dynamics reflect cellular processes and the multifaceted patient phenotype.

We acknowledge the Research Council of Finland (331946, 363941 to VPH, 363616 to RR), Sigrid Jusélius Foundation, Cancer Foundation Finland, and Tampere University doctoral school for funding. We acknowledge Biocenter Finland for infrastructure support. BTG acknowledges Cancer Research UK Program Grant (DRCRPG-May21).