PXD048044

PXD048044 is an original dataset announced via ProteomeXchange.

Title	CDKL1 risk variants predispose to a connective tissue disorder with thoracic aortic aneurysm and dissection
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-09-18
AnnouncementXML	Submission_2025-09-18_13:40:06.510.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bente Siebels
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-21 07:37:35	ID requested
1	2025-09-09 08:31:02	announced
⏵ 2	2025-09-18 13:40:06	announced	2025-09-18: Updated project metadata.

Dataset with its publication pending

submitter keyword: CDKL1, cGMP signaling,Thoracic aortic aneurysm and dissection, arterial aneurysm and dissection, hereditary aortopathy, connective tissue disorder

Dr. Georg Rosenberger
contact affiliation	Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
contact email	rosenberger@uke.de
lab head
Bente Siebels
contact affiliation	Section for Mass spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf
contact email	b.siebels@uke.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD048044
     1. Label: PRIDE project
     2. Name: CDKL1 risk variants predispose to a connective tissue disorder with thoracic aortic aneurysm and dissection