Mutations in PDLIM5 are rare in dilated cardiomyopathy but are emerging as potential disease modifiers

Abstract

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved.This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM. Methods: We performed computational ranking of human genes based on coexpression with a predefined set of genes known to be associated with DCM, which allowed us to prioritize gene candidates for their likelihood of being involved in DCM. Top candidates will be checked for variants in the available whole-exome sequencing data of 142 DCM patients. RNA was isolated from cardiac biopsies to investigate gene expression. Results: PDLIM5 was classified as the top candidate. An interesting heterozygous variant (189_190delinsGG) was found in a DCM patient with a known pathogenic truncating TTN-variant. The PDLIM5 loss-of-function (LoF) variant affected all cardiac-specific isoforms of PDLIM5 and no LoF variants were detected in the same region in a control cohort of 26,000 individuals. RNA expression of PDLIM5 and its direct interactors (MYOT, LDB3, and MYOZ2) was increased in cardiac tissue of this patient, indicating a possible compensatory mechanism. The PDLIM5 variant cosegregated with the TTN-variant and the phenotype, leading to a high disease penetrance in this family. A second patient was an infant with a homozygous 10 kb-deletion of exon 2 in PDLIM5 resulting in early-onset cardiac disease, showing the importance of PDLIM5 in cardiac function. Conclusions: Heterozygous PDLIM5 variants are rare and therefore will not have a major contribution in DCM. Although they likely play a role in disease development as this gene plays a major role in contracting cardiomyocytes and homozygous variants lead to early-onset cardiac disease. Other environmental and/or genetic factors are probably necessary to unveil the cardiac phenotype in PDLIM5 mutation carriers.

EPB41L5 controls podocyte extracellular matrix assembly by adhesome-dependent force transmission

“…Proteomic analysis of EPB41L5-enriched IACs indicated that EPB41L5 facilitates the recruitment of myosin-II-dependent adhesion components such as ACTN4 and PDLIM5, thereby modulating the repertoire of individual IACs (Figure 6). PDLIM5 belongs to the enigma protein subfamily and contains an N-terminal PDZ domain as well as C-terminal LIM-domains, which enable linkage to a-Actinin and other proteins (Verdonschot et al, 2020). More recently, PDLIM5 and a-Actinin have been implicated in force transmission and mechano-transduction signaling at IACs (Elbediwy et al, 2018;Ajeian et al, 2016;Meacci et al, 2016;Feng et al, 2018;Roca-Cusachs et al, 2013).…”

Full-Length Spatial Transcriptomics Reveals the Unexplored Isoform Diversity of the Myocardium Post-MI

“…The largest number of isoformswitching genes were found between the infarct and the remote zones (Figure 4B). Among them, we found PDZ and LIM domain protein 5 (Pdlim5), a gene encoding for a protein that localizes to the Z-disk by binding to α-actinin, and which has been implicated in dilated cardiomyopathy (Verdonschot et al, 2020) and in heart failure with preserved ejection fraction (Soetkamp et al, 2021). Pdlim5 has several splice variants, clustered into long and short isoforms, which are dynamically regulated during heart development (Yamazaki et al, 2010).…”

Leukocyte Nuclear Morphology Alterations in Dilated Cardiomyopathy Caused by a Lamin AC Truncating Mutation (LMNA/Ser431*) Are Modified by the Presence of a LAP2 Missense Polymorphism (TMPO/Arg690Cys)

“…This suggests that the final phenotype is influenced by modifier genes and environmental factors. Among the modifier genes involved in this variability, both protein-coding variants and variants located within enhancers have been described as altering the phenotypic expression of cardiomyopathy-causing mutations [ 4 , 5 , 6 ].…”