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Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease.

ABSTRACT: The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes. Studies of patients and mouse genetic models have pointed to important roles for lamins and their associated proteins in the function of gastrointestinal organs, including liver and pancreas. We review the interactions and functions of the lamina in relation to the nuclear envelope and genome, the ways in which its dysfunction is thought to contribute to human disease, and possible avenues for targeted therapies.

SUBMITTER: Brady GF

PROVIDER: S-EPMC6038707 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease.

Brady Graham F GF Kwan Raymond R Bragazzi Cunha Juliana J Elenbaas Jared S JS Omary M Bishr MB

Gastroenterology 20180313 6

The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased t ...[more]

PMID: 29549040

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Project description:BackgroundDisease-linked missense mutations can alter a protein's function with fatal consequences for the affected individual. How a single amino acid substitution in a protein affects its properties, is difficult to study in the context of the cellular proteome, because mutant proteins can often not be traced in cells due to the lack of mutation-specific detection tools. Antibodies, however, with their exquisite epitope specificity permit the detection of single amino acid substitutions but are not available for the vast majority of disease-causing mutant proteins. One of the most frequently missense-mutated human genes is the LMNA gene coding for A-type lamins. Mutations in LMNA cause phenotypically heterogenous, mostly autosomal-dominant inherited diseases, termed laminopathies. The molecular mechanisms underlying the phenotypic heterogeneity of laminopathies, however, are not well understood. Hence, the goal of this study was the development of monoclonal antibodies specific for disease-linked point-mutant A-type lamins.Methodology/principal findingsUsing two different approaches of antigen presentation, namely KLH-coupled peptides and the display of a complete protein domain fused to the Hepatitis B virus capsid protein, we developed monoclonal antibodies against two disease-associated lamin A/C mutants. Both antibodies display exquisite specificity for the respective mutant proteins. We show that with the help of these novel antibodies it is now possible for the first time to study specifically the properties of the mutant proteins in primary patient cells in the background of wild-type protein.ConclusionsWe report here the development of two point-mutant specific antibodies against A-type lamins. While synthetic peptides may be the prime choice of antigen, our results show that a given target sequence may have to be presented in alternative ways to ensure the induction of a mutant-specific immune response. Point-mutant specific antibodies will represent valuable tools for basic and clinical research on a number of hereditary as well as acquired diseases caused by dominant missense mutations.

Dataset Information

Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease.

Publications

Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease.

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