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Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1.

Authors
  • Peeters, Kristien1
  • Palaima, Paulius1
  • Pelayo-Negro, Ana L2
  • García, Antonio3
  • Gallardo, Elena4
  • García-Barredo, Rosario4
  • Mateiu, Ligia1
  • Baets, Jonathan1, 5, 6
  • Menten, Björn6
  • De Vriendt, Els1
  • De Jonghe, Peter1
  • Timmerman, Vincent1
  • Infante, Jon2
  • Berciano, José2
  • Jordanova, Albena1
  • 1 VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. , (Belgium)
  • 2 Departments of Neurology, University Hospital, University of Cantabria, and Center for Biomedical Research in the Neurodegenerative Diseases Network, Santander, Spain. , (Spain)
  • 3 Clinical Neurophysiology, University Hospital, University of Cantabria, and Center for Biomedical Research in the Neurodegenerative Diseases Network, Santander, Spain. , (Spain)
  • 4 Radiology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria, and Center for Biomedical Research in the Neurodegenerative Diseases (CIBERNED) Network, Santander, Spain. , (Spain)
  • 5 Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. , (Belgium)
  • 6 Born-Bunge Institute, University of Antwerp, Antwerp, Belgium. , (Belgium)
Type
Published Article
Journal
Annals of Neurology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2016
Volume
80
Issue
6
Pages
823–833
Identifiers
DOI: 10.1002/ana.24775
PMID: 27686364
Source
Medline
Language
English
License
Unknown

Abstract

To identify the unknown genetic cause in a large pedigree previously classified with a distinct form of axonal Charcot-Marie-Tooth disease type 2G (CMT2G) and to explore its transcriptional consequences. Clinical reevaluation of the pedigree was performed, followed by linkage analysis with the redefined disease statuses, and whole genome and exome sequencing. The impact of the mutation was investigated by immunoblotting and transcriptome sequencing. Thirteen affected individuals over 3 generations displayed mild and quiescent lower-limb axonal sensorimotor neuropathy. Magnetic resonance imaging (MRI) of lower-limb musculature systematically showed fatty atrophy in clinical and subclinical mutation carriers. We redefined the disease-linked region to chr9q31.3-q34.2 and subsequently identified a novel missense variant in the E3 ubiquitin-protein ligase LRSAM1 (p.Cys694Tyr). Unlike previous reports, we demonstrated in patients' lymphoblasts that the mutation does not influence overall protein levels of LRSAM1, nor of its ubiquitylation target TSG101. The mutation is associated with several transcriptional changes, including a significant upregulation of another E3 ubiquitin-protein ligase, NEDD4L, and of TNFRSF21, a key regulator of axonal degeneration. Our findings demonstrate that the isolated genetic entity CMT2G is caused by a missense mutation in LRSAM1 and should be reclassified as CMT2P. MRI of lower-limb musculature can be used to detect minimal signs of the disease. Transcriptome analysis of patients' cells highlights novel molecular players associated with LRSAM1 dysfunction, and reveals pathways and therapeutic targets shared with amyotrophic lateral sclerosis and Alzheimer disease. Ann Neurol 2016;80:823-833. © 2016 American Neurological Association.

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