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

ABSTRACT: Genetic factors are fundamental in the etiology of thoracic aortic aneurysm and dissection (TAAD), but the genetic cause is detected in only about 30% of cases. To define unreported TAAD-associated sequence variants, exome and gene panel sequencing was performed in 323 patients. We identified heterozygous CDKL1 variants [c.427T>C p.(Cys143Arg), c.617C>T p.(Ser206Leu), and c.404C>T p.(Thr135Met)] in 6 patients from 3 families with TAAD-spectrum disorders. CDKL1 encodes a protein kinase involved in ciliary biology. Amino acid substitutions were predicted to affect CDKL1 catalytic activity or protein binding properties. CDKL1 was expressed in vascular smooth muscle cells in normal and diseased human aortic wall tissue. Cdkl1 knockdown and transient knockout in zebrafish resulted in intersomitic vessel (ISV) malformations and aortic dilation. Co-injection of human CDKL1wildtype, but not CDKL1Cys143Arg and CDKL1Ser206Leu RNA, rescued ISV malformations. All variants affected CDKL1 kinase function and profiling data, and altered protein-protein binding properties, particularily with ciliary transport molecules. Expression of CDKL1 variants in heterologeous cells interfered with cilia formation and length, CDKL1 localization, and p38-MAPK and Vegf signaling. Our data suggest a role of CDKL1 variants in the pathogenesis of TAAD-spectrum disorders. The association between primary cilia dysregulation and TAAD expands our knowledge of the underlying molecular pathophysiology.

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

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	210511_sh_TN_CDK_1.raw	Raw
	210511_sh_TN_CDK_2.raw	Raw
	210511_sh_TN_CDK_3.raw	Raw
	210511_sh_TN_CDK_4.raw	Raw
	210511_sh_TN_CDK_5.raw	Raw

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