Universität zu Köln

Hanses, Ulrich, Kleinsorge, Mandy, Roos, Lennart, Yigit, Goekhan, Li, Yun, Barbarics, Boris, El-Battrawy, Ibrahim, Lan, Huan, Tiburcy, Malte, Hindmarsh, Robin, Lenz, Christof, Salinas, Gabriela, Diecke, Sebastian, Mueller, Christian, Adham, Ibrahim, Altmueller, Janine, Nuernberg, Peter, Paul, Thomas, Zimmermann, Wolfram-Hubertus, Hasenfuss, Gerd, Wollnik, Bernd and Cyganek, Lukas ORCID: 0000-0001-9120-1382 (2020). Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy. Circulation, 142 (11). S. 1059 - 1077. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4539

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Abstract

Background: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS-mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. Methods: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 (LZTR1). We generated induced pluripotent stem cell-derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level. Results: Patients' induced pluripotent stem cell-derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS-mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype. Conclusions: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell-derived cardiomyocytes from NS patients carrying biallelic variants inLZTR1and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hanses, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Kleinsorge, Mandy UNSPECIFIED UNSPECIFIED UNSPECIFIED Roos, Lennart UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Barbarics, Boris UNSPECIFIED UNSPECIFIED UNSPECIFIED El-Battrawy, Ibrahim UNSPECIFIED UNSPECIFIED UNSPECIFIED Lan, Huan UNSPECIFIED UNSPECIFIED UNSPECIFIED Tiburcy, Malte UNSPECIFIED UNSPECIFIED UNSPECIFIED Hindmarsh, Robin UNSPECIFIED UNSPECIFIED UNSPECIFIED Lenz, Christof UNSPECIFIED UNSPECIFIED UNSPECIFIED Salinas, Gabriela UNSPECIFIED UNSPECIFIED UNSPECIFIED Diecke, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Adham, Ibrahim UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Paul, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Wolfram-Hubertus UNSPECIFIED UNSPECIFIED UNSPECIFIED Hasenfuss, Gerd UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Cyganek, Lukas UNSPECIFIED orcid.org/0000-0001-9120-1382 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-319075
DOI:	10.1161/CIRCULATIONAHA.119.044794
Journal or Publication Title:	Circulation
Volume:	142
Number:	11
Page Range:	S. 1059 - 1077
Date:	2020
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4539
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PLURIPOTENT STEM-CELLS; MUTATIONS CAUSE NOONAN; OF-FUNCTION MUTATIONS; HYPERTROPHIC CARDIOMYOPATHY; RARE VARIANTS; UNDERLIE; RAS; CARDIOMYOCYTES; SARCALUMENIN; REGULATORS Multiple languages Cardiac & Cardiovascular Systems; Peripheral Vascular Disease Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31907