Insights into the molecular pathogenesis of cardiospondylocarpofacial syndrome: MAP3K7 c.737-7A > G variant alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy

Biochim Biophys Acta Mol Basis Dis. 2020 Jun 1;1866(6):165742. doi: 10.1016/j.bbadis.2020.165742.

Lucia Micale ¹, Silvia Morlino ², Tommaso Biagini ³, Annalucia Carbone ⁴, Carmela Fusco ⁵, Marco Ritelli ⁶, Vincenzo Giambra ⁷, Nicoletta Zoppi ⁶, Grazia Nardella ⁸, Angelantonio Notarangelo ⁵, Annalisa Schirizzi ⁹, Gianluigi Mazzoccoli ⁴, Paola Grammatico ², Emma M Wade ¹⁰, Tommaso Mazza ³, Marina Colombi ⁶, Marco Castori ⁵

Affiliations

1 Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy. Electronic address: [email protected].
2 Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
3 Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
4 Division of Internal Medicine and Unit of Chronobiology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
5 Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
6 Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
7 Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
8 Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
9 Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy; Dipartimento di Biologia, Università degli Studi di Bari, "Aldo Moro", Bari, Italy.
10 Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

PMID: 32105826 DOI: 10.1016/j.bbadis.2020.165742

Abstract

Transforming growth factor beta-activated kinase 1 (TAK1) is a highly conserved kinase protein encoded by MAP3K7, and activated by multiple extracellular stimuli, growth factors and cytokines. Heterozygous variants in MAP3K7 cause the cardiospondylocarpofacial syndrome (CSCFS) which is characterized by short stature, dysmorphic facial features, cardiac septal defects with valve dysplasia, and skeletal anomalies. CSCFS has been described in seven patients to date and its molecular pathogenesis is only partially understood. Here, the functional effects of the MAP3K7 c.737-7A > G variant, previously identified in a girl with CSCFS and additional soft connective tissue features, were explored. This splice variant generates an in-frame insertion of 2 amino acid residues in the kinase domain of TAK1. Computational analysis revealed that this in-frame insertion alters protein dynamics in the kinase activation loop responsible for TAK1 autophosphorylation after binding with its interactor TAB1. Co-immunoprecipitation studies demonstrate that the ectopic expression of TAK1-mutated protein impairs its ability to physically bind TAB1. In patient's fibroblasts, MAP3K7 c.737-7A > G variant results in reduced TAK1 autophosphorylation and dysregulation of the downstream TAK1-dependent signaling pathway. TAK1 loss-of-function is associated with an impaired TGFβ-mediated α-SMA Cytoskeleton assembly and cell migration, and defective Autophagy process. These findings contribute to our understanding of the molecular pathogenesis of CSCFS and might offer the rationale for the design of novel therapeutic targets.

Keywords

Cardiospondylocarpofacial syndrome; Connective tissue; TAB1; TAK1; TGFβ; α-SMA cytoskeleton.

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