Universität zu Köln

Ganapathi, Mythily ORCID: 0000-0003-2834-0843, Argyriou, Loukas, Martinez-Azorin, Francisco ORCID: 0000-0001-6250-7745, Morlot, Susanne, Yigit, Gokhan, Lee, Teresa M., Auber, Bernd, von Gise, Alexander, Petrey, Donald S., Thiele, Holger ORCID: 0000-0002-0169-998X, Cyganek, Lukas ORCID: 0000-0001-9120-1382, Sabater-Molina, Maria ORCID: 0000-0003-1352-1748, Ahimaz, Priyanka, Cabezas-Herrera, Juan, Sorli-Garcia, Moises, Zibat, Arne, Siegelin, Markus D., Burfeind, Peter, Buchovecky, Christie M., Hasenfuss, Gerd, Honig, Barry, Li, Yun, Iglesias, Alejandro D. and Wollnik, Bernd (2020). Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis. Hum. Genet., 139 (11). S. 1443 - 1455. NEW YORK: SPRINGER. ISSN 1432-1203

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ganapathi, Mythily UNSPECIFIED orcid.org/0000-0003-2834-0843 UNSPECIFIED Argyriou, Loukas UNSPECIFIED UNSPECIFIED UNSPECIFIED Martinez-Azorin, Francisco UNSPECIFIED orcid.org/0000-0001-6250-7745 UNSPECIFIED Morlot, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Gokhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Teresa M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Auber, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED von Gise, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Petrey, Donald S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED orcid.org/0000-0002-0169-998X UNSPECIFIED Cyganek, Lukas UNSPECIFIED orcid.org/0000-0001-9120-1382 UNSPECIFIED Sabater-Molina, Maria UNSPECIFIED orcid.org/0000-0003-1352-1748 UNSPECIFIED Ahimaz, Priyanka UNSPECIFIED UNSPECIFIED UNSPECIFIED Cabezas-Herrera, Juan UNSPECIFIED UNSPECIFIED UNSPECIFIED Sorli-Garcia, Moises UNSPECIFIED UNSPECIFIED UNSPECIFIED Zibat, Arne UNSPECIFIED UNSPECIFIED UNSPECIFIED Siegelin, Markus D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Burfeind, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Buchovecky, Christie M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hasenfuss, Gerd UNSPECIFIED UNSPECIFIED UNSPECIFIED Honig, Barry UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Iglesias, Alejandro D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-330379
DOI:	10.1007/s00439-020-02188-6
Journal or Publication Title:	Hum. Genet.
Volume:	139
Number:	11
Page Range:	S. 1443 - 1455
Date:	2020
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MUTATION; GENERATION Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33037