Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis

Hum Genet. 2020 Nov;139(11):1443-1454. doi: 10.1007/s00439-020-02188-6.

Mythily Ganapathi ¹, Loukas Argyriou ², Francisco Martínez-Azorín ³, Susanne Morlot ⁴, Gökhan Yigit ², Teresa M Lee ⁵, Bernd Auber ⁴, Alexander von Gise ⁶, Donald S Petrey ⁷, Holger Thiele ⁸, Lukas Cyganek ⁹, María Sabater-Molina ¹⁰, Priyanka Ahimaz ⁵, Juan Cabezas-Herrera ¹¹, Moisés Sorlí-García ¹², Arne Zibat ², Markus D Siegelin ¹³, Peter Burfeind ², Christie M Buchovecky ¹⁴, Gerd Hasenfuss ⁹, Barry Honig ¹⁵, Yun Li ², Alejandro D Iglesias ⁵, Bernd Wollnik ¹⁶ ¹⁷

Affiliations

1 Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, 10032, USA. [email protected].
2 Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.
3 Grupo de Enfermedades Raras, Mitocondriales y Neuromusculares (ERMN), Instituto de Investigación Hospital 12 de Octubre (i+12), 28041, Madrid, Spain.
4 Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
5 Department of Pediatrics, Columbia University Irving Medical Center, Columbia, 10032, USA.
6 Department of Pediatric Cardiology and Critical Care, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
7 Department of Systems Biology, Columbia University Irving Medical Center, 1130 Nicholas Ave, Columbia, 10032, USA.
8 Cologne Center for Genomics, University of Cologne, Weyertal 115b, 50931, Cologne, Germany.
9 Clinic for Cardiology and Pneumology, University Medical Center Göttingen, German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
10 Department of Cardiology, Hospital Clínico Universitario Virgen de la, Arrixaca, IMIB-Arrixaca, Murcia, Spain.
11 Molecular Therapy and Biomarkers Research Group, Hospital Clínico Universitario Virgen de La Arrixaca, IMIB-Arrixaca, Murcia, Spain.
12 Department of Pediatric Cardiology, Hospital Clínico Universitario Virgen de La Arrixaca, 30120, Murcia, Spain.
13 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, 10032, USA.
14 Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, 10032, USA.
15 Department of Systems Biology, Biochemistry and Molecular Biophysics, Medicine, Zuckerman Institute, Columbia University Irving Medical Center, 1130 Nicholas Ave, New York, 10032, USA.
16 Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany. [email protected].
17 Cluster of Excellence Multiscale Bioimaging from: Molecular Machines to Networks of Excitable Cells (MBExC), University of Göttingen, Göttingen, Germany. [email protected].

PMID: 32514796 DOI: 10.1007/s00439-020-02188-6

Abstract

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in Cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.

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