Lamin A/C Mutation Affecting Primarily the Right Side of the Heart

Laura Ollila,Johanna Kuusisto,Bjarne Udd,Keijo Peuhkurinen,Miia Holmström,Markku Saksa,Tiina Heliö,Satu Kärkkäinen,Petri Tuomainen,Annukka Lahtinen,Jarkko Magga,Olayinka Raheem,Janne Rapola,Elisabeth Widén,Sari Kivistö,Maija Kaartinen,Eero Lehtonen

doi:10.4081/cardiogenetics.2013.e1

Abstract

LMNA mutations are amongst the most important causes of familial dilated cardiomyopathy. The most important cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) is desmosomal pathology. The aim of the study was to elucidate the role of LMNA mutations among Finnish cardiomyopathy patients. We screened 135 unrelated cardiomyopathy patients for LMNA mutations. Because of unusual phenotype, two patients were screened for the known Finnish ARVC-related mutations of desmosomal genes, and their Plakophilin-2b gene was sequenced. Myocardial samples from two patients were examined by immunohistochemical plakoglobin staining and in one case by electron microscopy. We found a new LMNA mutation Phe237Ser in a family of five affected members with a cardiomyopathy affecting primarily the right side of the heart. The phenotype resembles ARVC but does not fulfill the Task Force Criteria. The main clinical manifestations of the mutation were severe tricuspid insufficiency, right ventricular enlargement and failure. Three of the affected patients died of the heart disease, and the two living patients received heart transplants at ages 44 and 47. Electron microscopy showed nuclear blebbing compatible with laminopathy. Immunohisto - chemical analysis did not suggest desmosomal pathology. No desmosomal mutations were found. The Phe237Ser LMNA mutation causes a phenotype different from traditional cardiolaminopathy. Our findings suggest that cardiomyopathy affecting primarily the right side of the heart is not always caused by desmosomal pathology. Our observations highlight the challenges in classifying cardiomyopathies, as there often is significant overlap between the traditional categories.

Highlights

Idiopathic dilated cardiomyopathy (DCM) is characterized by left ventricular dilatation and impaired systolic function in the absence of hypertension, coronary artery disease, valvular disease or other apparent cause
Genes shown to cause DCM can be grouped by function or cellular location into nuclear envelope proteins, such as Lamin A/C (LMNA), emerin and nesprin, cytoskeletal proteins such as dystrophin, and sarcomere genes such as myosin heavy chain and troponin T.3
Carriers of Lamin A/C mutations have been shown to be at a high risk of ventricular arrhythmias and sudden death.[9,10] important causes of familial dilated cardiomy- patients receiving a genetic diagnosis for their Arrhythmogenic right ventricular cardiomyopathy

Summary

Introduction

Idiopathic dilated cardiomyopathy (DCM) is characterized by left ventricular dilatation and impaired systolic function in the absence of hypertension, coronary artery disease, valvular disease or other apparent cause. Carriers of Lamin A/C mutations have been shown to be at a high risk of ventricular arrhythmias and sudden death.[9,10] important causes of familial dilated cardiomy- patients receiving a genetic diagnosis for their Arrhythmogenic right ventricular cardiomyopathy. The proband carrying a Lamin A/C mutation c.1442 dup A (pedigree shown in Figure 3) has never fully fulfilled the criteria for DCM; the course of her heart disease has been quite typical to laminopathy starting with atrial fibrillation at 41 and a non-sustained ventricular tachycardia and an implantable cardioverter-. The proband has a second brother (III:3) who has no symptoms of heart disease He turned out to be the only family member who is not a carrier of the new Lamin A/C mutation

PM No No No

Findings

Truncations of titin causing dilated carthy with advanced atrioventricular block