Khokhar, Noreen;
(2025)
Using human induced pluripotent stem cells to
elucidate lineage-specific phenotypes of
laminopathies.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Laminopathies are a group of heterogeneous disorders caused by mutations in the LMNA gene. LMNA encodes type V intermediate filament proteins Lamin A and C, which form the nuclear lamina along with Lamin B1 and B2. Laminopathies are tissue-specific disorders affecting peripheral nerve, adipose tissue, and striated muscle, with most laminopathy patients experiencing a cardiac phenotype. Laminopathies can also have systemic effects, for example in progeroid syndrome. Genotype-phenotype correlations remain unclear as the same mutation in LMNA can result in different laminopathies. Whilst there has been some progress in uncovering the mechanisms resulting in tissue-specific phenotypes in striated muscle, other affected tissue types are yet to be elucidated. Induced pluripotent stem cells (iPSCs), derived from laminopathy patients, were used to determine lineage-specific phenotypes of laminopathies. iPSCs were differentiated into affected cell types including motor neurons, cardiomyocytes, skeletal myotubes and endothelial cells. Perturbed nuclear morphology – a key disease-associated phenotype of LMNA-mutant cells – was studied to determine if nuclear morphology could be used as a phenotypic readout for investigating laminopathies, along with determining the lineage-specificity of various LMNA mutations. Results show that nuclear perturbations were present in LMNA-mutant skeletal myotubes and absent from motor neurons, indicating that nuclear abnormalities are lineage-specific. Moreover, LMNA-mutant iPSC derivatives did not alter apoptosis and LMNA-mutant motor neurons did not exhibit axonal defects. Finally, LMNA expression dynamics in iPSC derivatives were studied and it was found that motor neurons express very low or negligible levels of Lamin A/C in vitro. This finding indicates that low levels of mutant Lamin A/C during motor neuron specification could induce LMNA-related peripheral neuropathy, or that key pathogenic events have onset either during early or late neurogenesis, when LMNA is expressed at higher levels, as demonstrated using adult human spinal cord tissue containing mature motor neurons.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Using human induced pluripotent stem cells to elucidate lineage-specific phenotypes of laminopathies |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10213576 |
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