Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder. The most common mutation is a c.2204+6T>C transition in the 5' splice site (5'ss) of IKBKAP intron 20, which causes a tissue-specific skipping of exon 20, resulting in lower synthesis of IKAP/hELP1 protein. To better understand the specificity of neuron loss in FD, we modeled the molecular mechanisms of IKBKAP mRNA splicing by studying human olfactory ecto-mesenchymal stem cells (hOE-MSCs) derived from FD patient nasal biopsies. We explored how the modulation of IKBKAP mRNA alternative splicing impacts the transcriptome at the genome-wide level. We found that the FD transcriptional signature was highly associated with biological functions related to the development of the nervous system. In addition, we identified target genes of kinetin, a plant cytokinin that corrects IKBKAP mRNA splicing and increases the expression of IKAP/hELP1. We identified this compound as a putative regulator of splicing factors and added new evidence for a sequence-specific correction of splicing. In conclusion, hOE-MSCs isolated from FD patients represent a promising avenue for modeling the altered genetic expression of FD, demonstrating a methodology that can be applied to a host of other genetic disorders to test the therapeutic potential of candidate molecules.
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Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia.
Nat Commun
July 2021
Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Approximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5' splice site due to the IVS20 + 6 T > C mutation.
View Article and Find Full Text PDFUncommon side effects of common drugs in patients with familial dysautonomia.
Pharmacoepidemiol Drug Saf
February 2022
Department of Molecular Biology, Ariel University, Ariel, Israel.
Purpose: Patients with the autosomal recessive disorder of familial dysautonomia typically exhibit exacerbated adverse side effects to many common drugs. We aimed to catalog these adverse effects - with a focus on common drugs that are frequently administered to FD patients and compare their incidences to those within the general population.
Methods: We used data of 595 FD patients from an international database with information on drugs received and adverse effects.
The coexistence of a novel WNK1 variant and a copy number variation causes hereditary sensory and autonomic neuropathy type IIA.
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Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
Background: Hereditary sensory and autonomic neuropathy (HSAN) type II is a group of extremely rare autosomal recessive neurological disorders with heterogeneous clinical and genetic characteristics.
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The tumor necrosis factor (TNF)/TNF receptor (TNFR) pathway is known to influence survival of patients with cancer. We hypothesize that single nucleotide polymorphisms (SNPs) in the TNF/TNFR pathway genes related to apoptosis are associated with survival of patients with non-small cell lung cancer (NSCLC). We used 1185 patients with NSCLC in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study as the discovery and validation datasets, respectively.
View Article and Find Full Text PDFELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia.
Am J Hum Genet
April 2019
Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA. Electronic address:
Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in Elongator complex protein 1 (ELP1, also known as IKBKAP); this mutation leads to variable skipping of exon 20 and to a drastic reduction of ELP1 in the nervous system. Clinically, many of the debilitating aspects of the disease are related to a progressive loss of proprioception; this loss 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.
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