A Novel Mutation in Lamin A/C Gene: Phenotype and Consequences on the Protein Structure and Flexibility

Abstract

Laminopathies are a heterogeneous group of LMNA gene alteration-related disorders including muscular dystrophies, peripheral neuropathies, progeria, lipodystrophies, mandibuloacral dysplasia and restrictive dermopathy. We recently identified a family displaying mild skeletal muscle compromise and contractures and complaining of cardiac symptoms associated to a novel mutation consisting in c.388 G/T exon 2 LMNA gene substitution. The aim of the study was to assess the pathogenic effect of this mutation by means of computational experiments. The c.388 G/T mutation is a missense mutation causing the substitution of the amino acid Alanine with Serine in position 130 of the protein sequence of the coiled-coil region of Lamin A rod domain. Computational predictions and molecular dynamic simulation of lamin filaments revealed a 50% reduction in the probability of the sequence adopting a coiled-coil conformation. The present study provides a feasible explanation for the potential pathogenic effect of the novel c.388 G/T exon 2 LMNA gene mutation. The simulation revealed how the mutation alters the flexibility of lamin filaments and likely determines an impairment in the constitution of the coiled-coil structure.

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Copyright

Copyright © 2010 Nicola Carboni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.