Schirmer, Eric

Sewry, Caroline

Le, Thanh Phu

Medical Research Council (MRC)

2018-03-22T10:40:53Z

2018-03-22T10:40:53Z

2017-07-07

Many tissue-restricted diseases are linked to mutations in lamins and nuclear envelope transmembrane proteins (NETs). How these mutations in ubiquitously expressed proteins cause such defined diseases is still unknown. It is hypothesized that tissue restricted NETs that are partners of the nuclear lamins/existing linked proteins mediate tissue-specific disease pathologies. Proteomic studies have identified many tissue restricted NETs with effects on the cytoskeleton, gene positioning and regulation. This study investigates potential roles of candidate NETs in mediating tissue restricted disease pathology and their interactions with known factors such as emerin and lamins, mutations in which have been linked to a variety of tissue-specific dystrophies. This study looks into candidate tissue-specific NETs distribution in human tissues and in vitro using a solid phase binding assay to study candidate NETs interactions. I confirmed the tissue-specificity of the candidate NETs in human and mouse tissue sections but did not find clear reproducible distribution of these NETs in patient tissue biopsy. One postulate is that NETs bind WT lamin for localisation and/or function and disruption of this interaction leads to disease. Using a solid phase binding assay approach to study NETs/lamin interactions, we demonstrate that Tmem120a, an adipocyte-specific NET binds WT lamin but has a reduced Bmax when tested for binding against a lipodstrophy causing lamin mutant (R482Q and G465D). This is consistent with the hypothesis that tissue-specific NET partners might mediate tissue-specific disease pathology in lamin-linked nuclearenvelopathies.

http://hdl.handle.net/1842/28905

en

The University of Edinburgh

Meinke, P., P. Schneiderat, V. Srsen, N. Korfali, P. Le Thanh, G. J. Cowan, D. R. Cavanagh, M. Wehnert, E. C. Schirmer, and M. C. Walter. 2015. "Abnormal proliferation and spontaneous differentiation of myoblasts from a symptomatic female carrier of X-linked Emery-Dreifuss muscular dystrophy." Neuromuscul Disord no. 25 (2):127-36. doi: 10.1016/j.nmd.2014.09.012.

Peter Meinke, Alexandr A Makarov, Phú Lê Thành, Daina Sadurska, Eric C Schirmer. 2015. "Nucleoskeleton dynamics and functions in health and disease." Cell Health and Cytoskeleton (7):55-69.

Robson, M. I., J. I. de Las Heras, R. Czapiewski, P. Le Thanh, D. G. Booth, D. A. Kelly, S. Webb, A. R. Kerr, and E. C. Schirmer. 2016. "Tissue-Specific Gene Repositioning by Muscle Nuclear Membrane Proteins Enhances Repression of Critical Developmental Genes during Myogenesis." Mol Cell no. 62 (6):834-47. doi: 10.1016/j.molcel.2016.04.035.

NE proteins

NE-linked diseases

muscular dystrophy

lamins

NETs distribution

Nuclear envelope transmembrane proteins as mediators of tissue-specific diseases

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy