Nuclear envelope transmembrane proteins as mediators of tissue-specific diseases
Abstract
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.