CDKL1 risk variants predispose to a connective tissue disorder with thoracic aortic aneurysm and dissection

ABSTRACT: Genetic risk factors play a fundamental role in the etiology of thoracic aortic aneurysm and dissection (TAAD). More than 40 disease or risk genes for connective tissue disorders (CTD) characterized by TAAD have been described, however, about 70% of patients genetically remain undiagnosed. We aimed to identify novel sequence variants involved in the etiology of TAAD. Exome sequencing in three affected members of a family with TAAD identified the missense variant CDKL1 c.430T>C p.(Cys144Arg). Gene panel sequencing of 420 individuals with TAAD spectrum disorders revealed three CDKL1 missense variants, c.407C>T p.(Thr136Met) in an individual with aortic dissection, c.423T>G p.(Ile141Met) in a patient with aortic aneurysm and skeletal anomalies, as well as c.620C>T p.(Ser207Leu) in two siblings with ectasia of the aortic bulb, Marfan syndrome-like features and a family history of TAAD. Furthermore, exome sequencing identified the c.335T>C p.(Leu112Pro) missense variant in a female with bilateral vertebral artery dissection. CDKL1 encodes a barely investigated serine/threonine protein kinase involved in ciliary biology and cyclic guanosine monophosphate (cGMP) signaling. The predicted amino acid substitutions localize adjacent to/in the ATP binding domain [p.(Thr136Met), p.(Ile141Met) and p.(Cys144Arg)] or substrate-binding motifs [p.(Leu112Pro), p.(Ser207Leu)] of CDKL1. Knockdown of zcdkl1 in zebrafish lead to malformations of inter somatic vessels (ISV). Co-injection of human CDKL1WT RNA, but not of CDKL1C144R and CDKL1S207L RNA rescued ISV malformations. CDKL1 p.Cys144Arg-, p.Ser207Leu-, and p.Thr136Met expressed in heterologous cells interfered with CDKL1 kinase function and resulted in significantly altered kinase profiles compared to CDKL1WT protein. Kinase upstream analysis suggested a hyper-activation of nitric oxide (NO)-cGMP-protein kinase G (PRKG)-mediated and calcium (Ca2+)/calmodulin (CaM)-depending cellular signaling routes. Furthermore, disease-associated variants interfered with the length of primary cilia and the localization of CDKL1 at primary cilia, and it affected overall protein-complexing/protein-protein binding properties of CDKL1, especially with proteins involved in intraflagellar transport to cilia. Finally, expression of endogenous CDKL1 was demonstrated in cells positive for the multipotential mesenchymal stromal cell/multipotential precurser cell marker STRO-1 around Vasa vasorum in human aortic tissue. Taken together, genetic, clinical and functional data strongly suggest a role of CDKL1 variants in the pathogenesis of CTD with pronounced vascular involvement. Our data highlight that dysregulated signaling through NO, cGMP, and PRKG is critical to the etiology of TAAD/arterial dissection.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Bente Siebels  

LAB HEAD: Dr. Georg Rosenberger

PROVIDER: PXD048044 | Pride | 2025-09-09

REPOSITORIES: Pride