Research Article | Open Access
Nicola Carboni, Matteo Floris, Maria Valentini, Giovanni Marrosu, Eleonora Cocco, Maria Antonietta Maioli, Elisabetta Solla, Anna Mateddu, Marco Mura, Maria Giovanna Marrosu, "A Novel Mutation in Lamin A/C Gene: Phenotype and Consequences on the Protein Structure and Flexibility", SRX Biology, vol. 2010, Article ID 301679, 7 pages, 2010. https://doi.org/10.3814/2010/301679
A Novel Mutation in Lamin A/C Gene: Phenotype and Consequences on the Protein Structure and Flexibility
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.
- D. Z. Fisher, N. Chaudhary, and G. Blobel, “cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 17, pp. 6450–6454, 1986.
- G. Bonne, “Disease associated with myonuclear abnormalities: defects of nuclear membrane related proteins (emerin, lamins a/c),” in Structural and Molecular Basis of Skeletal Muscle Diseases, G. Karpati, Ed., chapter 3, pp. 48–56, ISN Neuropath Press, Basel, Switzerland, 2002.
- S. V. Strelkov, H. Herrmann, and U. Aebi, “Molecular architecture of intermediate filaments,” BioEssays, vol. 25, no. 3, pp. 243–251, 2003.
- S. V. Strelkov, J. Schumacher, P. Burkhard, U. Aebi, and H. Herrmann, “Crystal structure of the human lamin a coil 2B dimer: implications for the head-to-tail association of nuclear lamins,” Journal of Molecular Biology, vol. 343, no. 4, pp. 1067–1080, 2004.
- C. A. Brown, R. W. Lanning, K. Q. McKinney et al., “Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy,” American Journal of Medical Genetics, vol. 102, no. 4, pp. 359–367, 2001.
- B. Burke and C. L. Stewart, “Life at the edge: the nuclear envelope and human disease,” Nature Reviews Molecular Cell Biology, vol. 3, no. 8, pp. 575–585, 2002.
- M. Cohen, Y. Gruenbaum, K. K. Lee, and K. L. Wilson, “Transcriptional repression, apoptosis, human disease and the functional evolution of the nuclear lamina,” Trends in Biochemical Sciences, vol. 26, no. 1, pp. 41–47, 2001.
- N. M. Maraldi, C. Capanni, E. Mattioli et al., “A pathogenic mechanism leading to partial lipodistrophy and prospects for pharmacological treatment of insulin resistance syndrome,” Acta Bio-Medica, vol. 78, supplement 1, pp. 207–215, 2007.
- V. Stierlé, J. Couprie, C. Östlund et al., “The carboxyl-terminal region common to lamins A and C contains a DNA binding domain,” Biochemistry, vol. 42, no. 17, pp. 4819–4828, 2003.
- K. N. Jacob and A. Garg, “Laminopathies: multisystem dystrophy syndromes,” Molecular Genetics and Metabolism, vol. 87, no. 4, pp. 289–302, 2006.
- G. Bonne, E. Mercuri, A. Muchir et al., “Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene,” Annals of Neurology, vol. 48, no. 2, pp. 170–180, 2000.
- R. A. Hegele, “LMNA mutation position predicts organ system involvement in laminopathies,” Clinical Genetics, vol. 68, no. 1, pp. 31–34, 2005.
- S. Benedetti, I. Menditto, M. Degano et al., “Phenotypic clustering of lamin A/C mutations in neuromuscular patients,” Neurology, vol. 69, no. 12, pp. 1285–1292, 2007.
- T. A. Smith, P. M. Steinert, and D. A. D. Parry, “Modeling effects of mutations in coiled-coil structures: case study using epidermolysis bullosa simplex mutations in segment 1A of K5/K14 intermediate filaments,” Proteins: Structure, Function, and Bioinformatics, vol. 55, no. 4, pp. 1043–1052, 2004.
- M. Liovic, P. E. Bowden, R. Marks, and R. Komel, “A mutation (N177S) in the structurally conserved helix initiation peptide motif of keratin 5 causes a mild EBS phenotype,” Experimental Dermatology, vol. 13, no. 5, pp. 332–334, 2004.
- J. John, “Grading of muscle power: comparison of MRC and analogue scales by physiotherapists,” International Journal of Rehabilitation Research, vol. 7, no. 2, pp. 173–181, 1984.
- V. Dubowitz and C. Sewry, Muscle Biopsy: A Practical Approach, Saunders Book, St. Louis, MO, USA, 2007.
- L. V. B. Anderson and K. Davison, “Multiplex western blotting system for the analysis of muscular dystrophy proteins,” American Journal of Pathology, vol. 154, no. 4, pp. 1017–1022, 1999.
- E. Mercuri, A. Pichiecchio, S. Counsell et al., “A short protocol for muscle MRI in children with muscular dystrophies,” European Journal of Paediatric Neurology, vol. 6, no. 6, pp. 305–307, 2002.
- S. Sookhoo, I. MacKinnon, K. Bushby, P. F. Chinnery, and D. Birchall, “MRI for the demonstration of subclinical muscle involvement in muscular dystrophy,” Clinical Radiology, vol. 62, no. 2, pp. 160–165, 2007.
- J. Sambrook, E. Fritsch, T. Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory Press Cold Spring, Harbor, NY, USA, 1989.
- A. Sali and T. L. Blundell, “Comparative protein modelling by satisfaction of spatial restraints,” Journal of Molecular Biology, vol. 234, no. 3, pp. 779–815, 1993.
- J. C. Phillips, R. Braun, W. Wang et al., “Scalable molecular dynamics with NAMD,” Journal of Computational Chemistry, vol. 26, no. 16, pp. 1781–1802, 2005.
- N. Foloppe and A. D. MacKerell Jr., “All-atom empirical force field for nucleic acids: I. Parameter optimization based on small molecule and condensed phase macromolecular target data,” Journal of Computational Chemistry, vol. 21, no. 2, pp. 86–104, 2000.
- W. L. DeLano, The PyMOL Molecular Graphics System, DeLano Scientific, San Carlos, Calif, USA, 2002.
- V. A. Fischetti, G. M. Landau, P. H. Sellers, and J. P. Schmidt, “Identifying periodic occurences of a template with applications to protein structure,” Information Processing Letters, vol. 45, no. 1, pp. 11–18, 1993.
- A. Lupas, M. Van Dyke, and J. Stock, “Predicting coiled coils from protein sequences,” Science, vol. 252, no. 5010, pp. 1162–1164, 1991.
- E. Wolf, P. S. Kim, and B. Berger, “MultiCoil: a program for predicting two- and three-stranded coiled coils,” Protein Science, vol. 6, no. 6, pp. 1179–1189, 1997.
- M. A. Larkin, G. Blackshields, N. P. Brown et al., “Clustal W and Clustal X version 2.0,” Bioinformatics, vol. 23, no. 21, pp. 2947–2948, 2007.
- N. Carboni, M. Mura, G. Marrosu et al., “Muscle MRI findings in patients with an apparently exclusive cardiac phenotype due to a novel LMNA gene mutation,” Neuromuscular Disorders, vol. 18, no. 4, pp. 291–298, 2008.
- Lamin A/C (LMNA) sequence variations, “Leiden Muscular Dystrophy pages,” 2008, http://www.dmd.nl/.
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.