Mouse models for Familial Dysautonomia reveal underlying cellular & molecular mechanisms that cause the human disease


Frances Lefcort, Marta Chaverra, Lynn George, George Carleson, Miranda Orr, Andrea Grindeland


International Journal of Developmental Neuroscience


Hereditary sensory and autonomic neuropathies (HSANs) are a group of five phenotypically diverse but overlapping disorders of the peripheral nervous system (PNS) that result from mutations in 12 distinct genes. HSAN type III, or Familial Dysautonomia (FD), results from an intronic mutation (IVS20 + 6T > C; 99.5% of patients) in the gene, inhibitor of kappa B kinase complex-associated protein or IKBKAP, causing mis-splicing and subsequent tissue specific reductions in IKAP protein. It is both a developmental and progressive degenerative condition. FD is marked by tachycardia, blood pressure lability, autonomic vomiting “crises,” decreased pain and temperature sensation, and commonly death during early adulthood. The function of IKAP in the nervous system is unclear. Mice that are null for Ikbkap are embryonic lethal by E10 with a failure in neurulation and vasculogenesis. To obviate this early death, we generated two lines of mice in which Ikbkap is conditionally deleted, one of which uses a Wnt1-cre driver to delete Ikbkap in the neural crest lineage. These mice die within 24 h of birth and recapitulate such hallmarks of FD as significant reductions in neurons in the dorsal root, sympathetic and parasympathetic ganglia (George et al., PNAS, 2013). Our second mouse line uses a Ta1tubulin cre to delete Ikbkap from neurons. To our chagrin, this particular cre driver proved to be expressed throughout the CNS but not in the PNS. Since their PNS is not directly impacted, these mice do not die at birth, but instead live for up to 6 months. Strikingly, these mice develop a progressive degenerative condition that recapitulates several hallmarks of FD including scoliosis, hind limb weakness, ataxia, small size and sudden death. We will present our data on the cellular and molecular mechanisms responsible for both phenotypes and their potential for identifying targets for therapeutics to prevent the progressive degenerative stages of FD.



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