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GENATLAS PHENOTYPE
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
    eye
    Type disease
    Gene product
    Name IKBKAP, inhibitor of kappa light polypeptide gene
    Mechanism(s)
    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))