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Capturing the biology of mild versus severe disease in a pluripotent stem cell-based model of Familial Dysautonomia

ABSTRACT: Familial Dysautonomia is a genetic disease, however patietns with the same genotype present with mild or severe forms of the disease. We used the pluripotent stem cell technology to capture the differences in disease severity in vitro during neurodevelopment as well as during maintanance of the cells, showing developmental and degenerative phenotypes. RNA seq. analysis of the groups confirmed those diffferences.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77513 | GEO | 2016/11/14

SECONDARY ACCESSION(S): PRJNA310674

REPOSITORIES: GEO

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Capturing the Biology of Mild Versus Severe Disease in a Pluripotent Stem Cell-Based Model of Familial Dysautonomia

Project description:Capturing the Biology of Mild Versus Severe Disease in a Pluripotent Stem Cell-Based Model of Familial Dysautonomia

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Capturing the biology of disease severity in a PSC-based model of familial dysautonomia.

Project description:Familial dysautonomia (FD) is a debilitating disorder that affects derivatives of the neural crest (NC). For unknown reasons, people with FD show marked differences in disease severity despite carrying an identical, homozygous point mutation in IKBKAP, encoding IκB kinase complex-associated protein. Here we present disease-related phenotypes in human pluripotent stem cells (PSCs) that capture FD severity. Cells from individuals with severe but not mild disease show impaired specification of NC derivatives, including autonomic and sensory neurons. In contrast, cells from individuals with severe and mild FD show defects in peripheral neuron survival, indicating that neurodegeneration is the main culprit for cases of mild FD. Although genetic repair of the FD-associated mutation reversed early developmental NC defects, sensory neuron specification was not restored, indicating that other factors may contribute to disease severity. Whole-exome sequencing identified candidate modifier genes for individuals with severe FD. Our study demonstrates that PSC-based modeling is sensitive in recapitulating disease severity, which presents an important step toward personalized medicine.

| S-EPMC5555047 | biostudies-literature

Disease Severity in Familial Dysautonomia

Project description:<p>Familial Dysautonomia (FD) is a developmental and degenerative genetic disease that manifests in the neural crest cells and peripheral nervous system (PNS). Despite all FD patients having the same mutation in <i>IKBKAP</i>, patients present with varying disease severity, ranging from mild to severe. We used the human pluripotent stem cell technology to recapitulate this varying disease severity in the dish. Further, we found that severe, but not mild patients harbor mutations in candidate modifier genes that may contribute to severe disease presentation.</p>

| phs001233 | dbGaP

RNA sequencing of hiPSC derived neural crest populations from Familial Dysautonomia patients

2016-10-25 | GSE67073 | GEO

Effects of IKAP/hELP1 deficiency on gene expression in differentiating neuroblastoma cells, implications for Familial dysautonomia

Project description:Investigate IKAP importance in the development of neuronal cells, in order to understand Familial dysautonomia phenotype.

2011-01-06 | GSE26458 | GEO

Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration

Project description:Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration

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Transcription profiling by array of human olfactory ecto-mesenchymal stem cells in familial dysautonomia

Project description:Exploration of transcriptome expression in 5 control and 4 familial dysautonomia (FD) human olfactory ecto-mesenchymal stem cells (hOE-MSCs) at very early (P1 and P2) and later (P5 and P9) cell passages.

2011-01-01 | E-MTAB-281 | biostudies-arrayexpress

RNA sequencing of hiPSC derived neural crest populations from Familial Dysautonomia patients

Project description:We have generated expression profiles of induced pluripotent stem cells (iPSCs) and iPSC-derived neural crest populations from Familial Dysautonomia patients. These profiles were compared to a normal iPSC line that does not harbor the IKBKAP mutation. All cell types were differentiated from patient derived iPSCs. Bulk iPSCs were harvested for RNA and the neural crest populations were sorted on day 18 for p75/HNK1 before RNA isolation.

2016-10-25 | E-GEOD-67073 | biostudies-arrayexpress

Effects of IKAP/hELP1 deficiency on gene expression in differentiating neuroblastoma cells, implications for Familial dysautonomia

Project description:Investigate IKAP importance in the development of neuronal cells, in order to understand Familial dysautonomia phenotype. Stable SHSY5Y cell lines, and control cells, in differentiated and un-differentiated conditions.

2011-01-06 | E-GEOD-26458 | biostudies-arrayexpress

ELP1 splicing correction reverses proprioceptive sensory loss in familial dysautonomia

Project description:Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in Elongator complex protein 1 (ELP1, also known as IKBKAP) which leads to variable skipping of exon 20 and to a drastic reduction of ELP1 levels in the nervous system. Clinically, many of the debilitating aspects of the disease are related to a progressive loss of proprioception, which leads to severe gait ataxia, spinal deformities and respiratory insufficiency due to neuromuscular incoordination. There is currently no effective treatment for FD and the disease is ultimately fatal. Development of a drug that targets the underlying molecular defect provides hope that the drastic peripheral neurodegeneration characteristic of FD can be halted. We demonstrate herein that the FD mouse, TgFD9; IkbkapΔ20/flox, recapitulates the proprioceptive impairment observed in individuals with FD, and we provide the in vivo evidence that postnatal correction of mutant ELP1 splicing promoted by the small molecule kinetin can rescue neurological phenotypes in FD. Daily administration of kinetin starting at birth improves sensory-motor coordination and prevents the onset of spinal abnormalities by stopping the loss of proprioceptive neurons. These phenotypic improvements correlate with increased levels of full length ELP1 mRNA and protein in multiple tissues including the peripheral nervous system (PNS). Our results show that postnatal correction of the underlying ELP1 splicing defect can rescue devastating disease phenotypes and is therefore a viable therapeutic approach for persons with FD.

2019-03-21 | GSE126155 | GEO

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