Nuclear envelopathies and dysregulation of the cellular stress response

Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope and nuclear pore proteins. We have recently described two rare genetic diseases associated with defects in human lamina-associated polypeptide 1 (LAP1) and nucleoporin Nup214.

Homozygosity for a nonsense mutation in the TOR1AIP1 gene results in the combined loss of protein isoforms LAP1B and LAP1C. Patients present at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality. Patient-derived fibroblasts exhibit changes in nuclear envelope morphology, including reduced anti-lamin A/C nuclear rim staining intensity and large nuclear-spanning channels containing trapped cytoplasmic organelles. Functional cellular impairment is demonstrated by decreased and inefficient directional as well as random cell motility.

Biallelic missense and frameshift mutations in the NUP214 gene cause acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. Nuclear transport assays exhibit defects in the classical protein import and mRNA export pathways in patient-derived fibroblasts. Direct surface imaging of fibroblast nuclei by scanning electron microscopy reveals a large increase in the presence of central particles (or ‘‘plugs’’) in the nuclear pore channels of patient cells. This suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function in patient cells.

Patient-derived primary skin fibroblasts from both diseases show multiple signs of perturbations in homeostasis and dysregulated cellular stress response. This will be discussed in a wider context of clinical symptoms and potential effects in different cell types.