title: Merlin isoform 2 in neurofibromatosis type 2-associated polyneuropathy.
abstract: The autosomal dominant disorder neurofibromatosis type 2 (NF2) is a hereditary tumor syndrome caused by inactivation of the NF2 tumor suppressor gene, encoding merlin. Apart from tumors affecting the peripheral and central nervous systems, most NF2 patients develop peripheral neuropathies. This peripheral nerve disease can occur in the absence of nerve-damaging tumors, suggesting an etiology that is independent of gross tumor burden. We discovered that merlin isoform 2 (merlin-iso2) has a specific function in maintaining axonal integrity and propose that reduced axonal NF2 gene dosage leads to NF2-associated polyneuropathy. We identified a merlin-iso2-dependent complex that promotes activation of the GTPase RhoA, enabling downstream Rho-associated kinase to promote neurofilament heavy chain phosphorylation. Merlin-iso2-deficient mice exhibited impaired locomotor capacities, delayed sensory reactions and electrophysiological signs of axonal neuropathy. Sciatic nerves from these mice and sural nerve biopsies from NF2 patients revealed reduced phosphorylation of the neurofilament H subunit, decreased interfilament spacings and irregularly shaped axons.
authors: Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany.
authors: Alexander
authors: A
authors: Schulz
authors: Stephan L
authors: SL
authors: Baader
authors: Michiko
authors: M
authors: Niwa-Kawakita
authors: Marie Juliane
authors: MJ
authors: Jung
authors: Reinhard
authors: R
authors: Bauer
authors: Cynthia
authors: C
authors: Garcia
authors: Ansgar
authors: A
authors: Zoch
authors: Stephan
authors: S
authors: Schacke
authors: Christian
authors: C
authors: Hagel
authors: Victor-Felix
authors: VF
authors: Mautner
authors: C Oliver
authors: CO
authors: Hanemann
authors: Xin-Peng
authors: XP
authors: Dun
authors: David B
authors: DB
authors: Parkinson
authors: Joachim
authors: J
authors: Weis
authors: J Michael
authors: JM
authors: Schröder
authors: David H
authors: DH
authors: Gutmann
authors: Marco
authors: M
authors: Giovannini
authors: Helen
authors: H
authors: Morrison
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D016518:Neurofibromatosis 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011115:Polyneuropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology
chemical_list: D025581:Neurofibromin 2; D020033:Protein Isoforms