Genetics of Human Laminopathies

Lamins A/C, encoded by LMNA gene, are constituents of the nuclear lamina, a meshwork of proteins underneath the nuclear envelope. Human disorders linked to LMNA mutations are known as laminopathies and include cardiac and muscular dystrophies, lipodystrophies, progeroid syndromes and overlapping phenotypes. Associated with this wide clinical variability, there is also a large allelic heterogeneity that is still expanding. New links between LMNA mutations and human diseases with already known or unknown molecular cause have been established. In other cases, no evidence that a human disease is another laminopathy has been found. Moreover, the recent availability of high-throughput sequencing technologies has made feasible to uncover the disease-causing mutations in patients who were originally diagnosed with laminopathies but whose mutational analysis of candidate gene did not reveal any change in LMNA. Key Concepts Mutations in the LMNA gene, encoding A-type lamin proteins, lead to a wide range of diseases known as laminopathies. The clinical and allelic heterogeneity of laminopathies is still expanding. Studies of the molecular mechanisms underlying laminopathies have led to advances in the understanding of lamin A functions and developing novel therapeutic strategies. A group of progeroid phenotypes is phenocopy of progeroid laminopathies. High-throughput sequencing technologies have made it possible to uncover the disease-causing mutations in genes that encode proteins involved in nuclear envelope architecture or in control of genomic stability. Nuclear alterations are linked to human ageing. Keywords: laminopathies; LMNA; lamin A/C; genetic heterogeneity; NGS