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last update : 07-05-2019
Symbol HSAN3
Location 9q31.3
Name hereditary sensory and autonomic neuropathy, type III
Other name(s)
  • Riley-Day syndrome
  • familial dysautonomia, hereditary
  • Corresponding gene ELP1
    Other symbol(s) DYSA, FD
    Main clinical features
  • characterized by lack of tearing, emotional hability, paroxysmal hypertension, increased sweating, cold hands and feet, corneal anesthesia and blotching of the skin
  • poor development and progressive degeneration of the sensory and autonomic nervous system with progressive blindness
  • many of the debilitating aspects of the disease are related to a progressive loss of proprioception, leading to severe gait ataxia, spinal deformities, and respiratory insufficiency due to neuromuscular incoordination (PMID: 30905397))
  • Genetic determination autosomal recessive
    Prevalence 1/3600 live births with a carrier frequency of 1 in 30 in the Ashkenazi Jewish
    Function/system disorder neurology
    Type disease
    Gene product
    Name IKBKAP, inhibitor of kappa light polypeptide gene
    Gene mutationChromosome rearrangementEffectComments
    abnormal splicing     mutation in exon 20 leading to aberrant splicing, IVS20+6T>C
    Remark(s) . point mutation leads to variable, tissue specific expression of a truncated IKBKAP mRNA, that coincides with a marked reduction of its wild type mRNA leading to decreased IKAP protein levels especially in the sensory and autonomous nervous system (Naumanen 2008)
  • single nucleotide (T→C) transition in the donor splice site of intron 20 leads to the skipping of exon 20 by alternative splicing, producing both wild-type and short (exon 20 skipped) transcripts in a tissue-specific manner with full exon 20 skipping and consequently elimination of the protein product in the nervous tissues (PMID: 21273291))
  • loss of ELP1 leads to neuron death as a consequence of failed target tissue innervation associated with impairments in cytoskeletal regulation (PMID: 24917501))
  • mutation leads to variable skipping of exon 20 and to a drastic reduction of IKBKAP in the nervous system (PMID: 30905397))
  • small molecule kinetin (6-furfurylaminopurine), is an orally active enhancer of IKBKAP splicing; increasing IKBKAP after birth, regardless of the therapeutic mechanism, will most likely rescue proprioceptive neurons and improve neurologic symptoms in HSAN3 (PMID: 30905397))