Of splice and men: what does the distribution of IKAP mRNA in the rat tell us about the pathogenesis of familial dysautonomia?

Brain Res. 2003 Sep 5;983(1-2):209-14. doi: 10.1016/s0006-8993(03)03090-7.

Abstract

Familial dysautonomia (FD) is the best-known and most common member of a group of congenital sensory/autonomic neuropathies characterized by widespread sensory and variable autonomic dysfunction. As opposed to the sensory/motor neuropathies, little is known about the causes of neuronal dysfunction and loss in the sensory/autonomic neuropathies. FD involves progressive neuronal degeneration, has a broad impact on the operation of many of the body's systems, and leads to a markedly reduced quality of life and premature death. In 2001, we identified two mutations in the IKBKAP gene that result in FD. IKBKAP encodes IKAP, a member of the putative human holo-Elongator complex, which may facilitate transcription by RNA polymerase II. Whether or not the Elongator plays this role is moot. The FD mutation found on >99.5% of FD chromosomes does not cause complete loss of function. Instead, it results in a tissue-specific decrease in splicing efficiency of the IKBKAP transcript; cells from patients retain some capacity to produce normal mRNA and protein. To better understand the relationship between the genotype of FD patients and their phenotype, we have used in situ hybridization histochemistry to map the IKAP mRNA in sections of whole rat embryos. The mRNA is widely distributed. Highest levels are in the nervous system, but substantial amounts are also present in peripheral organs.

MeSH terms

  • Animals
  • Autoradiography
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics*
  • Dysautonomia, Familial / genetics*
  • Embryo, Mammalian / metabolism
  • Embryonic and Fetal Development / physiology
  • Female
  • Gene Expression Regulation, Developmental / physiology
  • Humans
  • Pregnancy
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics*
  • RNA-Binding Proteins
  • Rats
  • Tissue Distribution
  • Transcriptional Elongation Factors

Substances

  • Carrier Proteins
  • Elp1 protein, human
  • Elp1 protein, rat
  • RNA, Messenger
  • RNA-Binding Proteins
  • Transcriptional Elongation Factors