Ulrich Hanses1, Mandy Kleinsorge1, Lennart Roos1, Gökhan Yigit2, Yun Li3, Boris Barbarics4, Ibrahim El-Battrawy5, Huan Lan6, Malte Tiburcy7, Robin Hindmarsh1, Christof Lenz8, Gabriela Salinas3, Sebastian Diecke9, Christian Müller3, Ibrahim Adham3, Janine Altmüller10, Peter Nürnberg10, Thomas Paul4, Wolfram-Hubertus Zimmermann11, Gerd Hasenfuss12, Bernd Wollnik13, Lukas Cyganek1. 1. Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany. 2. DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany; NGS Integrative Genomics Core Unit, Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany. 3. NGS Integrative Genomics Core Unit, Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany. 4. DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany; Clinic for Pediatric Cardiology and Intensive Care Medicine, University Medical Center Göttingen, Göttingen, Germany. 5. DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany; First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany. 6. First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany. 7. DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany. 8. Institute for Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany; Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. 9. DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany; Stem Cell Core Facility, Max Delbrück Center for Molecular Medicine, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. 10. Cologne Center for Genomics, University of Cologne, Cologne, Germany. 11. DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany. 12. Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany. 13. DZHK (German Center for Cardiovascular Research), partner site Göttingen, Mannheim and Berlin, Germany; NGS Integrative Genomics Core Unit, Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany.
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-MAP kinase (MAPK) 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 (HCM) as the clinically most prevalent symptom caused by biallelic mutations within the leucine zipper like transcription regulator 1 (LZTR1). We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of the affected siblings and investigated the patient-specific CMs on the molecular and functional level. Results: The patients' iPSC-CMs recapitulated the hypertrophic phenotype and uncovered a so far not described causal link between LZTR1 dysfunction, RAS-MAPK 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 repair and demonstrated a rescue of the hypertrophic phenotype. Conclusions: Our study revealed the human cardiac pathogenesis in patient-specific iPSC-CMs from NS patients carrying biallelic variants in LZTR1 and 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 HCM.
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-MAP kinase (MAPK) 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 (HCM) as the clinically most prevalent symptom caused by biallelic mutations within the leucine zipper like transcription regulator 1 (LZTR1). We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of the affected siblings and investigated the patient-specific CMs on the molecular and functional level. Results: The patients' iPSC-CMs recapitulated the hypertrophic phenotype and uncovered a so far not described causal link between LZTR1 dysfunction, RAS-MAPK 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 repair and demonstrated a rescue of the hypertrophic phenotype. Conclusions: Our study revealed the human cardiac pathogenesis in patient-specific iPSC-CMs from NSpatients carrying biallelic variants in LZTR1 and 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 HCM.
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