gms | German Medical Science

57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie (DGNN)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

12. - 15.09.2012, Erlangen

Banner: 57. Jahrestagung der Deutschen Gesellschaft für Neuropathologie und Neuroanatomie

Novel INF2 mutation links the FSGS-CMT associated pathophysiology to disturbances in ER homeostasis

Meeting Abstract

  • presenting/speaker Andreas Roos - University Hospital RWTH Aachen, Aachen, Germany; Friedrich-Baur-Institute, Munich, Germany
  • Stephan Buchkremer - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany
  • Eva Brauers - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany
  • Peter Boor - University Hospital RWTH Aachen, Institute of Pathology & Dpt. of Nephrology, Aachen, Germany
  • Jan Senderek - Friedrich-Baur-Institute, Munich, Germany
  • Martin Häusler - University Hospital RWTH Aachen, Dpt. of Neuropediatrics, Aachen, Germany
  • Joachim Weis - University Hospital RWTH Aachen, Institute of Neuropathology, Aachen, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Erlangen, 12.-15.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgnnPP1.6

DOI: 10.3205/12dgnn024, URN: urn:nbn:de:0183-12dgnn0243

Veröffentlicht: 11. September 2012

© 2012 Roos et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

INF2 (chromosome 14q32.22) encodes inverted formin 2, a member of the diaphanous-related formin family. This protein is found in the cytoplasm and in the endoplasmic reticulum. INF2 exhibits different domains promoting protein-protein-interactions. It binds to the myelin and lymphocyte protein MAL and interacts with the Rho-GTPase CDC42. Both proteins have been shown to be important for myelination and myelin maintenance. Initially, mutations in theINF2gene were found to cause focal segmental glomerulosclerosis (FSGS). Recently, mutations within the same gene were linked to FSGS-associated dominant Charcot-Marie-Tooth disease with prominent demyelination (especially onion bulb formations) and less severe axonal changes (Boyer et al., NEJM Dec 22;365:2377-88, 2011). Based on functional studies, Boyer and co-workers postulated a possible negative effect of mutant INF2 on endoplasmic reticulum (ER) morphology and homeostasis. We carried outINF2-mutational screening in a 15 years old girl suffering from FSGS-associated Charcot-Marie-Tooth disease and identified the so far unknown missense-mutation p.L77R (c.230T>G), located in the CDC42 binding domain. Extensive electron microscopical studies of sural nerve and and the gastrocnemius muscle revealed, in addition to the anticipated demyelinating changes, interesting alterations of ER morphology in both axons and Schwann cells. Examination of intramuscular nerve fascicles revealed that the motor nerve fibers are more affected than the sensory fibers. Even though the sarcoplasmic reticulum did not present with marked morphological alterations, numerous vacuoles, frequently associated with myonuclei, and deposits of accumulated autophagic material were found in the muscle biopsy specimen. The alterations in ER morphology as well as the detection of accumulated material in the affected tissue prompted us to focus on factors of the “unfolded protein response” in ongoing functional studies. We describe clinical, morphological and biochemical consequences of a novel INF2 mutation in a 15 years old female patient with FSGS-associated CMT. Our findings link the pathogenesis of FSGS-CMT disease to disturbances in ER homeostasis.