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

Carboni, Nicola; Floris, Matteo; Valentini, Maria; Marrosu, Giovanni; Cocco, Eleonora; Maioli, Maria Antonietta; Solla, Elisabetta; Mateddu, Anna; Mura, Marco; Marrosu, Maria Giovanna

doi:https://doi.org/10.3814/2010/301679

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Volume 2010 | Article ID 301679 | https://doi.org/10.3814/2010/301679

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

Nicola Carboni,¹Matteo Floris,²Maria Valentini,²Giovanni Marrosu,¹Eleonora Cocco,¹Maria Antonietta Maioli,¹Elisabetta Solla,¹Anna Mateddu,¹Marco Mura,³and Maria Giovanna Marrosu¹

Received21 Oct 2009

Revised07 Jan 2010

Accepted01 Feb 2010

Published15 Mar 2010

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.

References

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.
View at: Google Scholar
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.
View at: Google Scholar
S. V. Strelkov, H. Herrmann, and U. Aebi, “Molecular architecture of intermediate filaments,” BioEssays, vol. 25, no. 3, pp. 243–251, 2003.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Google Scholar
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.
View at: Publisher Site | Google Scholar
K. N. Jacob and A. Garg, “Laminopathies: multisystem dystrophy syndromes,” Molecular Genetics and Metabolism, vol. 87, no. 4, pp. 289–302, 2006.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
R. A. Hegele, “LMNA mutation position predicts organ system involvement in laminopathies,” Clinical Genetics, vol. 68, no. 1, pp. 31–34, 2005.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Google Scholar
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.
View at: Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Google Scholar
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.
View at: Publisher Site | Google Scholar | MathSciNet
A. Lupas, M. Van Dyke, and J. Stock, “Predicting coiled coils from protein sequences,” Science, vol. 252, no. 5010, pp. 1162–1164, 1991.
View at: Google Scholar
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.
View at: Google Scholar
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.
View at: Publisher Site | Google Scholar
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.
View at: Publisher Site | Google Scholar
Lamin A/C (LMNA) sequence variations, “Leiden Muscular Dystrophy pages,” 2008, http://www.dmd.nl/.
View at: Google Scholar

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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.

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