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Am J Hum Genet. 2019 Apr 4;104(4):638-650. doi: 10.1016/j.ajhg.2019.02.009. Epub 2019 Mar 21.

ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia.

Author information

1
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.
2
Center for Genomic Medicine, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
3
Department of Biological Sciences, Section of Neurobiology, University of Southern California, Los Angeles, CA 90089, USA.
4
Department of Physiology, the University of Tennessee, Health Science Center, Memphis, TN 38163, USA.
5
PTC Therapeutics, Inc., South Plainfield, NJ 07080, USA.
6
Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
7
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: slaugenhaupt@mgh.harvard.edu.

Abstract

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. The 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, promoted by the small molecule kinetin, of the mutant ELP1 splicing 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 amounts of full-length ELP1 mRNA and protein in multiple tissues, including in 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.

KEYWORDS:

ELP1; IKAP; familial dysautonomia; neurodegenerative disease; splicing; therapeutics

PMID:
30905397
PMCID:
PMC6451698
[Available on 2019-10-04]
DOI:
10.1016/j.ajhg.2019.02.009

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