Clinical Autonomic Research

, Volume 27, Issue 4, pp 235–243 | Cite as

Animal and cellular models of familial dysautonomia

  • Frances LefcortEmail author
  • Marc Mergy
  • Sarah B. Ohlen
  • Yumi Ueki
  • Lynn George


Since Riley and Day first described the clinical phenotype of patients with familial dysautonomia (FD) over 60 years ago, the field has made considerable progress clinically, scientifically, and translationally in treating and understanding the etiology of FD. FD is classified as a hereditary sensory and autonomic neuropathy (HSAN type III) and is both a developmental and a progressive neurodegenerative condition that results from an autosomal recessive mutation in the gene IKBKAP, also known as ELP1. FD primarily impacts the peripheral nervous system but also manifests in central nervous system disruption, especially in the retina and optic nerve. While the disease is rare, the rapid progress being made in elucidating the molecular and cellular mechanisms mediating the demise of neurons in FD should provide insight into degenerative pathways common to many neurological disorders. Interestingly, the protein encoded by IKBKAP/ELP1, IKAP or ELP1, is a key scaffolding subunit of the six-subunit Elongator complex, and variants in other Elongator genes are associated with amyotrophic lateral sclerosis (ALS), intellectual disability, and Rolandic epilepsy. Here we review the recent model systems that are revealing the molecular and cellular pathophysiological mechanisms mediating FD. These powerful model systems can now be used to test targeted therapeutics for mitigating neuronal loss in FD and potentially other disorders.


Familial dysautonomia IKBKAP Autonomic nervous system Neural development Neural degeneration 


Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.


  1. 1.
    Dietrich P, Dragatsis I (2016) Familial dysautonomia: mechanisms and models. Genet Mol Biol 39(4):497–514CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Norcliffe-Kaufmann L, Slaugenhaupt SA, Kaufmann H (2017) Familial dysautonomia: history, genotype, phenotype and translational research. Prog Neurobiol 152:131–148CrossRefPubMedGoogle Scholar
  3. 3.
    Axelrod FB (2006) A world without pain or tears. Clin Auton Res 16(2):90–97CrossRefPubMedGoogle Scholar
  4. 4.
    Norcliffe-Kaufmann L, Slaugenhaupt SA, Kaufmann H (2016) Familial dysautonomia: history, genotype, phenotype and translational research. Prog Neurobiol 152:131–148CrossRefPubMedGoogle Scholar
  5. 5.
    Mendoza-Santiesteban CE et al (2014) Selective retinal ganglion cell loss in familial dysautonomia. J Neurol 261(4):702–709CrossRefPubMedGoogle Scholar
  6. 6.
    Mendoza-Santiesteban CE et al (2012) Clinical neuro-ophthalmic findings in familial dysautonomia. J Neuroophthalmol 32(1):23–26CrossRefPubMedGoogle Scholar
  7. 7.
    Mendoza-Santiesteban CE et al. (2017) Pathologic confirmation of optic neuropathy in familial dysautonomia. J Neuropathol Exp Neurol 76(3):238–244CrossRefPubMedGoogle Scholar
  8. 8.
    Slaugenhaupt SA et al (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68(3):598–605CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Anderson SL et al (2001) Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet 68(3):753–758CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Boone N et al (2010) Olfactory stem cells, a new cellular model for studying molecular mechanisms underlying familial dysautonomia. PLoS One 5(12):e15590CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Huang B, Johansson MJ, Bystrom AS (2005) An early step in wobble uridine tRNA modification requires the Elongator complex. RNA 11(4):424–436CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Esberg A et al (2006) Elevated levels of two tRNA species bypass the requirement for elongator complex in transcription and exocytosis. Mol Cell 24(1):139–148CrossRefPubMedGoogle Scholar
  13. 13.
    Laguesse S et al (2015) A dynamic unfolded protein response contributes to the control of cortical neurogenesis. Dev Cell 35(5):553–567CrossRefPubMedGoogle Scholar
  14. 14.
    Nedialkova DD, Leidel SA (2015) Optimization of codon translation rates via tRNA modifications maintains proteome integrity. Cell 161(7):1606–1618CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Karlsborn T et al (2014) Familial dysautonomia (FD) patients have reduced levels of the modified wobble nucleoside mcmsU in tRNA. Biochem Biophys Res Commun 454(3):441–445CrossRefPubMedGoogle Scholar
  16. 16.
    Lin FJ et al (2013) Ikbkap/Elp1 deficiency causes male infertility by disrupting meiotic progression. PLoS Genet 9(5):e1003516CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yoshida M et al (2015) Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia. Proc Natl Acad Sci USA 112(9):2764–2769CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Otero G et al (1999) Elongator, a multisubunit component of a novel RNA polymerase II holoenzyme for transcriptional elongation. Mol Cell 3(1):109–118CrossRefPubMedGoogle Scholar
  19. 19.
    Wittschieben BO et al (1999) A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol Cell 4(1):123–128CrossRefPubMedGoogle Scholar
  20. 20.
    Rahl PB, Chen CZ, Collins RN (2005) Elp1p, the yeast homolog of the FD disease syndrome protein, negatively regulates exocytosis independently of transcriptional elongation. Mol Cell 17(6):841–853CrossRefPubMedGoogle Scholar
  21. 21.
    Gardiner J et al (2007) Potential role of tubulin acetylation and microtubule-based protein trafficking in familial dysautonomia. Traffic 8(9):1145–1149CrossRefPubMedGoogle Scholar
  22. 22.
    Solinger JA et al (2010) The Caenorhabditis elegans elongator complex regulates neuronal alpha-tubulin acetylation. PLoS Genet 6(1):e1000820CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Johansen LD et al (2008) IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration. J Cell Sci 121(Pt 6):854–864CrossRefPubMedGoogle Scholar
  24. 24.
    Lefler S et al (2015) Familial dysautonomia (FD) human embryonic stem cell derived PNS neurons reveal that synaptic vesicular and neuronal transport genes are directly or indirectly affected by IKBKAP downregulation. PLoS One 10(10):e0138807CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Naftelberg S et al (2016) Phosphatidylserine ameliorates neurodegenerative symptoms and enhances axonal transport in a mouse model of familial dysautonomia. PLoS Genet 12(12):e1006486CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tourtellotte WG (2016) Axon transport and neuropathy: relevant perspectives on the etiopathogenesis of familial dysautonomia. Am J Pathol 186(3):489–499CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    George L et al (2013) Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons. Proc Natl Acad Sci USA 110(46):18698–18703CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hunnicutt BJ et al (2012) IKAP/Elp1 is required in vivo for neurogenesis and neuronal survival, but not for neural crest migration. PLoS One 7(2):e32050CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jackson MZ et al (2014) A neuron autonomous role for the familial dysautonomia gene ELP1 in sympathetic and sensory target tissue innervation. Development 141(12):2452–2461CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Addis L et al (2015) Microdeletions of ELP4 are associated with language impairment, autism spectrum disorder, and mental retardation. Hum Mutat 36(9):842–850CrossRefPubMedGoogle Scholar
  31. 31.
    Simpson CL et al (2009) Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum Mol Genet 18(3):472–481CrossRefPubMedGoogle Scholar
  32. 32.
    Strug LJ et al (2009) Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4). Eur J Hum Genet 17(9):1171–1181CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kwee LC et al (2012) A high-density genome-wide association screen of sporadic ALS in US veterans. PLoS One 7(3):e32768CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Gkampeta A et al (2014) Association of brain-derived neurotrophic factor (BDNF) and elongator protein complex 4 (ELP4) polymorphisms with benign epilepsy with centrotemporal spikes in a Greek population. Epilepsy Res 108(10):1734–1739CrossRefPubMedGoogle Scholar
  35. 35.
    Reinthaler EM et al (2014) Analysis of ELP4, SRPX2, and interacting genes in typical and atypical rolandic epilepsy. Epilepsia 55(8):e89–e93CrossRefPubMedGoogle Scholar
  36. 36.
    Cohen JS et al (2015) ELP2 is a novel gene implicated in neurodevelopmental disabilities. Am J Med Genet A 167(6):1391–1395CrossRefPubMedGoogle Scholar
  37. 37.
    Kojic M, Wainwright B (2016) The many faces of elongator in neurodevelopment and disease. Front Mol Neurosci 9:115CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Abashidze A et al (2014) Involvement of IKAP in peripheral target innervation and in specific JNK and NGF signaling in developing PNS neurons. PLoS One 9(11):e113428CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Cheng WW et al (2015) Depletion of the IKBKAP ortholog in zebrafish leads to hirschsprung disease-like phenotype. World J Gastroenterol 21(7):2040–2046PubMedPubMedCentralGoogle Scholar
  40. 40.
    Singh N et al (2010) The histone acetyltransferase Elp3 plays in active role in the control of synaptic bouton expansion and sleep in Drosophila. J Neurochem 115(2):493–504CrossRefPubMedGoogle Scholar
  41. 41.
    Chen C, Tuck S, Bystrom AS (2009) Defects in tRNA modification associated with neurological and developmental dysfunctions in Caenorhabditis elegans elongator mutants. PLoS Genet 5(7):e1000561CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Walker J et al (2011) Role of elongator subunit Elp3 in Drosophila melanogaster larval development and immunity. Genetics 187(4):1067–1075CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Bar-Shai A et al (2004) Decreased density of ganglia and neurons in the myenteric plexus of familial dysautonomia patients. J Neurol Sci 220(1–2):89–94CrossRefPubMedGoogle Scholar
  44. 44.
    Yang X et al (2016) Elongator Protein 3 (Elp3) stabilizes Snail1 and regulates neural crest migration in Xenopus. Sci Rep 6:26238CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Hims MM et al (2007) A humanized IKBKAP transgenic mouse models a tissue-specific human splicing defect. Genomics 90(3):389–396CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Bochner R et al (2013) Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model. Hum Mol Genet 22(14):2785–2794CrossRefPubMedGoogle Scholar
  47. 47.
    Chen YT et al (2009) Loss of mouse Ikbkap, a subunit of elongator, leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKAP. Mol Cell Biol 29(3):736–744CrossRefPubMedGoogle Scholar
  48. 48.
    Dietrich P et al (2011) Deletion of exon 20 of the Familial Dysautonomia gene Ikbkap in mice causes developmental delay, cardiovascular defects, and early embryonic lethality. PLoS One 6(10):e27015CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Dietrich P et al (2012) IKAP expression levels modulate disease severity in a mouse model of familial dysautonomia. Hum Mol Genet 21(23):5078–5090CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Morini E et al. (2016) Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia. Hum Mol Genet 25(6):1116–1128CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lyst MJ, Bird A (2015) Rett syndrome: a complex disorder with simple roots. Nat Rev Genet 16(5):261–275CrossRefPubMedGoogle Scholar
  52. 52.
    Close P et al (2006) Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Mol Cell 22(4):521–531CrossRefPubMedGoogle Scholar
  53. 53.
    Naumanen T et al (2008) Loss-of-function of IKAP/ELP1: could neuronal migration defect underlie familial dysautonomia? Cell Adh Migr 2(4):236–239CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Chaverra M et al. (2017) The familial dysautonomia disease gene, Ikbkap/Elp1, is required in the developing and adult central nervous system. Dis Model Mech 10(5):605–618CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Axelrod FB et al (2010) Neuroimaging supports central pathology in familial dysautonomia. J Neurol 257(2):198–206CrossRefPubMedGoogle Scholar
  56. 56.
    Ochoa JG (2003) Familial dysautonomia (Riley-Day syndrome) may be associated with epilepsy. Epilepsia 44(3):472CrossRefPubMedGoogle Scholar
  57. 57.
    Ueki Y et al (2016) Loss of Ikbkap causes slow, progressive retinal degeneration in a mouse model of familial dysautonomia. eNeuro 3(5)Google Scholar
  58. 58.
    Carelli V, La Morgia C, Sadun AA (2013) Mitochondrial dysfunction in optic neuropathies: animal models and therapeutic options. Curr Opin Neurol 26(1):52–58CrossRefPubMedGoogle Scholar
  59. 59.
    Palma JA et al (2015) Increased frequency of rhabdomyolysis in familial dysautonomia. Muscle Nerve 52(5):887–890CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ohlen SB et al (2017) BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia. Proc Natl Acad Sci USA 114(19):5035–5040CrossRefPubMedGoogle Scholar
  61. 61.
    Lee G et al (2009) Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 461(7262):402–406CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Lee G et al (2012) Large-scale screening using familial dysautonomia induced pluripotent stem cells identifies compounds that rescue IKBKAP expression. Nat Biotechnol 30(12):1244–1248CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Valensi-Kurtz M et al (2010) Enriched population of PNS neurons derived from human embryonic stem cells as a platform for studying peripheral neuropathies. PLoS One 5(2):e9290CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Zeltner N et al (2016) Capturing the biology of disease severity in a PSC-based model of familial dysautonomia. Nat Med 22(12):1421–1427CrossRefPubMedGoogle Scholar
  65. 65.
    Boone N et al (2012) Genome-wide analysis of familial dysautonomia and kinetin target genes with patient olfactory ecto-mesenchymal stem cells. Hum Mutat 33(3):530–540CrossRefPubMedGoogle Scholar
  66. 66.
    Herve M, Ibrahim EC (2016) MicroRNA screening identifies a link between NOVA1 expression and a low level of IKAP in familial dysautonomia. Dis Model Mech 9(8):899–909CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Herve M, Ibrahim EC (2017) Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia. Neurobiol Dis 103:113–122CrossRefPubMedGoogle Scholar
  68. 68.
    Vierbuchen T et al (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463(7284):1035–1041CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Wainger BJ et al (2015) Modeling pain in vitro using nociceptor neurons reprogrammed from fibroblasts. Nat Neurosci 18(1):17–24CrossRefPubMedGoogle Scholar
  70. 70.
    Norcliffe-Kaufmann LJ, Axelrod FB, Kaufmann H (2013) Cyclic vomiting associated with excessive dopamine in Riley-Day syndrome. J Clin Gastroenterol 47(2):136–138CrossRefPubMedGoogle Scholar
  71. 71.
    Macefield VG et al (2016) Increasing cutaneous afferent feedback improves proprioceptive accuracy at the knee in patients with sensory ataxia. J Neurophysiol 115(2):711–716CrossRefPubMedGoogle Scholar
  72. 72.
    Macefield VG et al (2011) Can loss of muscle spindle afferents explain the ataxic gait in Riley-Day syndrome? Brain 134(Pt 11):3198–3208CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of Cell Biology and NeuroscienceMontana State UniversityBozemanUSA
  2. 2.Department of Biological and Physical SciencesMontana State University BillingsBillingsUSA

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