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Nuclear Envelope-linked Rare Human Diseases: From Molecular Pathophysiology towards Clinical Applications

Final Report Summary - EURO-LAMINOPATHIES (Nuclear Envelope-linked Rare Human Diseases: From Molecular Pathophysiology towards Clinical Applications)

The EURO-LAMINOPATHIES consortium brought together clinical and basic researchers as well as company-based research, aiming at understanding the molecular basis of a heterogeneous class of human diseases linked to mutations in lamins and lamin-associated proteins (known as laminopathies). Understanding lamin function in normal tissues and its dysfunction in diseased cells is crucial for identifying new drug targets and drugs for efficient therapeutic approaches, which was another major objective of the project.

Clinicians and human geneticists used the existing links to hospitals and genetic centres to expand their knowledge on disease phenotypes, genes and mutations involved in laminopathies. They collected, analysed and organised patient cells, tissues, and clinical and genetic information of patients and patient families. Using this information, several groups in the consortium generated and studied animal disease models (transgenic mice, C. elegans, zebrafish). They investigated potential disease mechanisms and explored possibilities how a pathological phenotype can be rescued.

Using patient cells and tissues, transgenic animals and cells derived there from, and isolated mutated and wild type proteins, the EURO-LAMINOPATHIES consortium has been testing the following disease hypothesis:
- the mechanical hypothesis, predicting that disease-causing mutations interfere with the atomic structure, assembly, and stability of lamins;
- the gene expression hypothesis suggesting that the expression of mutated lamin proteins alters chromatin organization and gene expression; and
- the cell differentiation / proliferation hypothesis proposing an impairment of tissue homeostasis and regeneration in patients.

The detailed analyses of these mechanisms is expected to yield potential new drug targets and will help to identify drugs, whose potential for treatment of a particular disease phenotype can be tested in the available animal and cellular models. Finally, existing therapies for laminopathy patients were further developed by the generation and use of theranostic tools in order to improve the efficiency of treatment and reduce side effects.

For lamin A/C (LMNA) mutations, new clinical subgroups were identified, i.e. insulin resistance syndromes atypical for familial partial lipodystrophy, Dunnigan type (FPLD) and severe congenital muscular dystrophies. We have also contributed to the description of fertility and obstetrical complications in women with LMNA-related familial partial lipodystrophy.

The consortium vividly transferred their newly generated knowledge on nuclear envelop-linked rare human diseases: from molecular pathophysiology towards clinical applications to the scientific community, industry, students, patient organisations, and to science journalists in numerous talks and posters at international conferences. Consortium members were invited for talks, seminars and lectures at national and international institutions, meetings and conferences. The young group members were especially encouraged to and did present their projects and results at the annual consortium meetings and at external conferences.