Autosomal Dominant Partial Lipodystrophy Research Articles

954 DILATED CARDIOMYOPATHY AND ATRIOVENTRICULAR BLOCK RELATED TO THE MUTATION IN THE LMNE GENE: DESCRIPTION OF A FAMILY

Abstract The proband was patient A2, suffering by severe left ventricular dysfunction (EF 20%) and II degree Mobitz type 1 atrioventricular block, requiring dual chamber ICD implantation, and retinitis pigmentosa. He had three brothers A1, A4, A5 suffering also by dilated cardiomyopathy and ICD/CRTD recipients. His sister A3, his daughter B1 and the firstborn brother A1 were also affected by retinitis pigmentosa. Genetic analysis was performed in A2 by NGS of a panel of genes related to heart disease and retinitis pigmentosa. It documented the presence of a missense pathogenetic variant (class 4) of the LMNA gene in heterozygosis (c.949G>A). This variant has been described in several scientific papers as associated with cardiac impairment in patients suffering from atrioventricular block and dilated cardiomyopathy. Laminin A/C is a fundamental protein of the nuclear envelope of the cell. Germline mutations in the LMNA gene, present on chromosome 22 (1q22), encoding the A/C lamina, have been causally linked to four different diseases with 42 reported mutations: Dilated cardiomyopathy (DCM) with disease of the conduction system; Limb girdle muscular dystrophy (LGMD); Autosomal dominant variant of Emery-Dreifuss muscular dystrophy (EDMD); Autosomal dominant partial lipodystrophy. LMNA-related dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and/or reduced systolic function frequently preceded or accompanied by significant conduction system disease. Family studies suggest that conduction system disease commonly precedes the development of DCM by a few years to a decade or more. Conduction system involvement usually starts with disease of the sinus node and/or atrioventricular node that can manifest as sinus bradycardia, sinus node arrest with junctional rhythms, or heart block (commonly first-degree heart block that progresses to second- and third-degree block). The following are also common: symptomatic bradyarrhythmias requiring cardiac pacemakers, supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome), ventricular arrhythmias including frequent premature ventricular contractions and ventricular tachycardia Sudden cardiac death may occur with progressive disease. Although more malignant, life-threatening arrhythmias may occur with longstanding and usually previously symptomatic DCM, sudden cardiac death can also be the presenting manifestation of LMNA-related DCM, with minimal or no left ventricular dysfunction. In the cardiological setting, the AVB associated with DCM is a reliable marker for LMNA gene molecular screening. Regarding retinitis pigmentosa, the variant in heterozygosis c538C>G was found in the RHO gene in the proband, classifiable as pathogenetic. This gene encodes a protein necessary for the function of retinal photoreceptors and pathogenic mutations have been found in 30-40% of hereditary forms of retinitis pigmentosa. In conclusion, we believe that the tests carried out confirmed the hypothesis of a hereditary form of cardiomyopathy and retinitis pigmentosa, which seem to segregate independently in the family. Both mutations can be transmitted in 50% of cases, regardless of sex. For this reason we recommended to extend genetic analysis to all the first-degree relatives (siblings and children).

A G613A missense in the Hutchinson’s progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block

BackgroundLMNA/C mutations have been linked to the premature aging syndrome Hutchinson’s progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease.One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this case, onset has been correlated with several mutations in genes essential for the proper maturation of cardiomyocytes, such as the gene for lamin A/C. However, no clear genotype–phenotype relationship has been reported to date between LMNA/C mutations and cardiomyopathies.ResultsDNA and medical histories were collected from (n = 11) members of different generations of one family, the proband of which was implanted with a pacemaker for lone, type II AVB. Exome sequencing analysis was performed on three relatives with AVB, and the mutations therein identified validated in a further three AVB-affected family members.In the initial three AVB family members, we identified 10 shared nonsynonymous single-nucleotide variations with a rare or unreported allele frequency in the 1000 Genomes Project database. Follow-up genetic screening in the additional three affected relatives disclosed a correlation between the lone AVB phenotype and the single-nucleotide polymorphism rs56816490, which generates an E317K change in lamin A/C. Although this mutation has already been described by others in a DCM-affected proband with familiarity for AVB and sudden death, the absence of DCM in our large, AVB-affected family is indicative of genotype–phenotype correlation between rs56816490 and a familial, autosomal dominant form of lone AVB.ConclusionsScreening for G613A in LMNA/C in patients with lone AVB and their relatives might prevent sudden death in families affected by AVB but without familiarity for DCM. Lone AVB is an age-related disease caused by mutations in LMNA/C gene rather than a complication of DCM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12979-014-0019-3) contains supplementary material, which is available to authorized users.

Homozygous Defects In Lmna, Encoding Lamin A/C Nuclear‐Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy In Human (Charcot‐Marie‐Tooth Disorder Type 2) And Mouse

The Charcot‐Marie‐Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve‐conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes‐NF‐L and KIF1Bbeta‐have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR‐CMT2) provided evidence of linkage to chromosome 1q21.2‐q21.3 in two families (Z(max) = 4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural explor‐ ation of sciatic nerves of LMNA null (i.e., −/−) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site‐specific amino acid substitutions in limb‐girdle muscular dystrophy type 1B, autosomal dominant Emery‐Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR‐CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1.

Homozygous Defects in LMNA, Encoding Lamin A/C Nuclear-Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy in Human (Charcot-Marie-Tooth Disorder Type 2) and Mouse

The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes---NF-L and KIF1Bbeta---have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Zmax=4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1.