Nuclear Lamins in Health and Disease
Nuclear lamins are key proteins in the mechanical functioning of cells. Especially, proteins from the LMNA gen (lamin A, lamin C and lamin Adel10) appear to determine cellular stiffness and mechanoresponse. Laminopathies arise in patients with LMNA mutations, with a disease phenotype ranging from Hutchison Gilford progeria to muscle and fat tissue–related disorders, such as dilated cardiomyopathy and partial lipodystrophy. In all, LMNA mutations lead to about 20 different clinical diseases, depending on the localisation of the mutation and as yet unknown additional factors in disease development.
In our group we study the cellular effects of LMNA mutations, using vital microscopy, advanced high-resolution microscopy (STED), Two-photon microscopy, as well as standard molecular techniques.
The impact of alterations in LMNA expression on mechanical properties of these cells is studied in close cooperation with Dr. Carlijn Bouten (Eindhoven University of Technology, Dept. of Biomedical engineering).
Detailed microscopic analyses of dermal fibroblast from patients with LMNA mutations will lead to functional assays to predict disease development. These studies are performed in close cooperation with dr. Arthur van den Wijngaard (Maastricht University, Dept. of Clinical genetics, Cardiogenetics).
The downregulation of A-type lamins leads to increased mobility of tumor cells, allowing improved capabilities of tumor invasion and metastasis. Together with Dr. Jürgen Becker (Translational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Germany) we investigate the impact of LMNA downregulation on the behavior of Merkel cell carcinomas.
- Assessment of fibroblast nuclear morphology aids interpretation of LMNA variants. van Tienen FHJ, Lindsey PJ, Kamps MAF, Krapels IP, Ramaekers FCS, Brunner HG, van den Wijngaard A, Broers JLV. Eur J Hum Genet. 2019 Mar;27(3):389-399.
- Select item 287901525.
- Lamin A/C-Related Cardiac Disease: Late Onset With a Variable and Mild Phenotype in a Large Cohort of Patients With the Lamin A/C p.(Arg331Gln) Founder Mutation. Hoorntje ET, Bollen IA, Barge-Schaapveld DQ, van Tienen FH, Te Meerman GJ, Jansweijer JA, van Essen AJ, Volders PG, Constantinescu AA, van den Akker PC, van Spaendonck-Zwarts KY, Oldenburg RA, Marcelis CL, van der Smagt JJ, Hennekam EA, Vink A, Bootsma M, Aten E, Wilde AA, van den Wijngaard A, Broers JL, Jongbloed JD, van der Velden J, van den Berg MP, van Tintelen JP. Circ Cardiovasc Genet. 2017 Aug;10(4).
- Lmna knockout mouse embryonic fibroblasts are less contractile than their wild-type counterparts. van Loosdregt IAEW, Kamps MAF, Oomens CWJ, Loerakker S, Broers JLV, Bouten CVC. Integr Biol (Camb). 2017 Aug 14;9(8):709-721.
- Cellular strain avoidance is mediated by a functional actin cap - observations in an Lmna-deficient cell model. Tamiello C, Halder M, Kamps MA, Baaijens FP, Broers JL, Bouten CV. J Cell Sci. 2017 Feb 15;130(4):779-790.
- Tamiello C, Buskermolen AB, Baaijens FP, Broers JLV, Bouten CV. Heading in the right direction: understanding cellular orientation responses to complex biophysical environments. Cell Mol Bioeng 9:12-37, 2016.
- Broers JL, Ramaekers FC. The role of the nuclear lamina in cancer and apoptosis. Adv Exp Med Biol 773:27-48, 2014.
- Tamiello C, Kamps MA, van den Wijngaard A, Verstraeten VL, Baaijens FP, Broers JL, Bouten CC. Soft substrates normalize nuclear morphology and prevent nuclear rupture in fibroblasts from a laminopathy patient with compound heterozygous LMNA mutations. Nucleus 4:61-73, 2013.
- De Vos WH, Houben F, Kamps M, Malhas A, Verheyen F, Cox J, Manders EM, Verstraeten VL, van Steensel MA, Marcelis CL, van den Wijngaard A, Vaux DJ, Ramaekers FC, Broers JL. Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum Mol Genet 20:4175-4186, 2011.
- Verstraeten VL, Broers JL, van Steensel MA, Zinn-Justin S, Ramaekers FC, Steijlen PM, Kamps M, Kuijpers HJ, Merckx D, Smeets HJ, Hennekam RC, Marcelis CL, van den Wijngaard A. Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation. Hum Mol Genet. 15:2509-2522, 2006.
- Broers JL, Ramaekers FC, Bonne G, Yaou RB, Hutchison CJ. Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev 86:967-1008, 2006.
- Broers JL, Peeters EA, Kuijpers HJ, Endert J, Bouten CV, Oomens CW, Baaijens FP, Ramaekers FC. Decreased mechanical stiffness in LMNA-/- cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies. Hum Mol Genet 13:2567-2580, 2004.
- Broers JL, Machiels BM, van Eys GJ, Kuijpers HJ, Manders EM, van Driel R, Ramaekers FC. Dynamics of the nuclear lamina as monitored by GFP-tagged A-type lamins. J Cell Sci. 112:3463-3475, 1999.