2. Academic Validation
  3. Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies

Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies

  • Am J Hum Genet. 2016 Sep 1;99(3):607-623. doi: 10.1016/j.ajhg.2016.07.008.
Michaela Auer-Grumbach 1,  Stefan Toegel 2,  Maria Schabhüttl 3,  Daniela Weinmann 2,  Catharina Chiari 2,  David L H Bennett 4,  Christian Beetz 5,  Dennis Klein 6,  Peter M Andersen 7,  Ilka Böhme 8,  Regina Fink-Puches 9,  Michael Gonzalez 10,  Matthew B Harms 11,  William Motley 12,  Mary M Reilly 13,  Wilfried Renner 14,  Sabine Rudnik-Schöneborn 15,  Beate Schlotter-Weigel 16,  Andreas C Themistocleous 17,  Jochen H Weishaupt 18,  Albert C Ludolph 18,  Thomas Wieland 19,  Feifei Tao 20,  Lisa Abreu 20,  Reinhard Windhager 2,  Manuela Zitzelsberger 16,  Tim M Strom 21,  Thomas Walther 22,  Steven S Scherer 12,  Stephan Züchner 20,  Rudolf Martini 6,  Jan Senderek 23
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Medical University of Vienna, Vienna 1090, Austria. Electronic address: [email protected].
  • 2 Department of Orthopaedics, Medical University of Vienna, Vienna 1090, Austria; Karl Chiari Lab for Orthopaedic Biology, Department of Orthopaedics, Medical University of Vienna, Vienna 1090, Austria.
  • 3 Department of Orthopaedics, Medical University of Vienna, Vienna 1090, Austria.
  • 4 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
  • 5 Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena 07745, Germany.
  • 6 Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Würzburg 97080, Germany.
  • 7 Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå 901 85, Sweden.
  • 8 Department of Pediatric Surgery, University of Leipzig, Leipzig 04103, Germany.
  • 9 Department of Dermatology, Medical University of Graz, Graz 8036, Austria.
  • 10 The Genesis Project Inc., Miami, FL 3136, USA.
  • 11 Department of Neurology, Columbia University, New York, NY 10032, USA.
  • 12 Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-6077, USA.
  • 13 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK.
  • 14 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria.
  • 15 Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
  • 16 Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich 80336, Germany.
  • 17 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK; Brain Function Research Group, School of Physiology, Faculty of Health Science, University of the Witwatersrand, Johannesburg 2193, South Africa.
  • 18 Neurology Department, Ulm University, Ulm 89081, Germany.
  • 19 Institute of Human Genetics, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Neuherberg 85764, Germany.
  • 20 Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
  • 21 Institute of Human Genetics, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Neuherberg 85764, Germany; Institute for Human Genetics, Technical University Munich, Munich 81675, Germany.
  • 22 Department of Pharmacology and Therapeutics, University College Cork, Cork T12 YT57, Ireland; Department of Obstetrics, University of Leipzig, Leipzig 04103, Germany.
  • 23 Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich 80336, Germany. Electronic address: [email protected].
PMID: 27588448 DOI: 10.1016/j.ajhg.2016.07.008
Abstract

Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease Neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of Neprilysin and impaired enzymatic activity. Although Neprilysin is known to degrade β-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate Neprilysin activity could be a rational option for treatment.

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