Abstract
Purpose. Retinopathy is an important manifestation of
trifunctional protein (TFP) deficiencies but not of other
defects of fatty acid oxidation. The common homozygous
mutation in the TFP a-subunit gene HADHA (hydroxyacyl-CoA
dehydrogenase), c.1528G>C, affects the long-chain
3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity of TFP
and blindness in infancy. The pathogenesis of the
retinopathy is unknown. This study aimed to utilize human
induced pluripotent stem cell (hiPSC) technology to
create a disease model for the disorder, and to derive
clues for retinopathy pathogenesis. Methods. We
implemented hiPSC technology to generate LCHAD deficiency
(LCHADD) patient-specific retinal pigment epithelial
(RPE) monolayers. These patient and control RPEs were
extensively characterized for function and structure, as
well as for lipid composition by mass spectrometry.
Results. The hiPSC-derived RPE monolayers of patients and
controls were functional, as they both were able to
phagocytose the photoreceptor outer segments in vitro.
Interestingly, the patient RPEs had intense cytoplasmic
neutral lipid accumulation, and lipidomic analysis
revealed an increased triglyceride accumulation. Further,
patient RPEs were small and irregular in shape, and their
tight junctions were disorganized. Their ultratructure
showed decreased pigmentation, few melanosomes, and more
melanolysosomes. Conclusions. We demonstrate that the RPE
cell model reveals novel early pathogenic changes in
LCHADD retinopathy, with robust lipid accumulation,
inefficient pigmentation that is evident soon after
differentiation, and a defect in forming tight junctions
inducing apoptosis. We propose that LCHADD-RPEs are an
important model for mitochondrial TFP retinopathy, and
that their early pathogenic changes contribute to
infantile blindness of LCHADD.
Original language | English |
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Pages (from-to) | 3371-3382 |
Journal | Investigative Ophthalmology and Visual Science |
Volume | 56 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2015 |
MoE publication type | A1 Journal article-refereed |
Keywords
- beta oxidation
- mitochondria
- retinal pigment epithelium
- retinopathy