Novel LMNA gene mutation in a patient with cardiac and skeletal muscle involvement

Lamins A and C are type V intermediate filament proteins, which are components of the nuclear envelope. Lamins A and C are transcribed from a single gene, LMNA, which is encoded on chromosome 1q21.2–q21.3. 29. LMNA mutations are associated with several diseases, including Emery-Dreifuss muscular dystrophy (EDMD), limbgirdle muscular dystrophy type 1B (LGMD1B), dilated cardiomyopathies (DCM) with conduction disease (CMD1A), Charcot-Marie- Tooth type 2, Hutchinson-Gilford progeria syndrome, familial partial lipodystrophy, restrictive dermopathy and mandibuloacral dysplasia, along with various overlapping phenotypes and rare variants. Objectives: We describe the case of a 58 years-old woman displaying dilated cardiomyopathy and skeletal muscle involvement, probably inherited as a dominant trait. Methods: The subject underwent muscle biopsy and genetic analysis of LMNA gene (performed by PCR amplification and analysis with Denaturing High Pressure Liquid Chromatography), leading to identification of a novel, heterozygous frameshift duplication in position c.1102_1130 of exon 6, promoting the formation of a premature stop codon in the putative protein. The genetic analysis was, therefore, extended to the patient’s son, which exhibited, since the age of 26, cardiac conduction disturbances, without skeletal muscle involvement. The same mutation was demonstrated. Results: To our knowledge, this is the first report of a duplication in the LMNA gene. These data confirm previous observations describing a predominance of frameshift mutations in patients with adult-onset cardiac disease. In addition, variants in these patients were mostly located in coil 2B, as in our case. Since it has been previously shown that lamin hetero and homodimers can form via coil 2 interactions, we had hypothesized that mutations involving residues in this domain may affect dimer formation or higher levels of lamin assembly and that late onset phenotypes may arise through a loss of function mechanism secondary to haploinsufficiency. Conclusion: Our observation further expands the type of LMNA mutations described in laminopathy patients, since a DNA duplication had not been identified before.