title: Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies.
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.
authors: Department of Orthopaedics, Medical University of Vienna, Vienna 1090, Austria. Electronic address: michaela.auer-grumbach@meduniwien.ac.at.
authors: Michaela
authors: M
authors: Auer-Grumbach
authors: 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.
authors: Stefan
authors: S
authors: Toegel
authors: Department of Orthopaedics, Medical University of Vienna, Vienna 1090, Austria.
authors: Maria
authors: M
authors: Schabhüttl
authors: 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.
authors: Daniela
authors: D
authors: Weinmann
authors: 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.
authors: Catharina
authors: C
authors: Chiari
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors: David L H
authors: DLH
authors: Bennett
authors: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena 07745, Germany.
authors: Christian
authors: C
authors: Beetz
authors: Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Würzburg 97080, Germany.
authors: Dennis
authors: D
authors: Klein
authors: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå 901 85, Sweden.
authors: Peter M
authors: PM
authors: Andersen
authors: Department of Pediatric Surgery, University of Leipzig, Leipzig 04103, Germany.
authors: Ilka
authors: I
authors: Böhme
authors: Department of Dermatology, Medical University of Graz, Graz 8036, Austria.
authors: Regina
authors: R
authors: Fink-Puches
authors: The Genesis Project Inc., Miami, FL 3136, USA.
authors: Michael
authors: M
authors: Gonzalez
authors: Department of Neurology, Columbia University, New York, NY 10032, USA.
authors: Matthew B
authors: MB
authors: Harms
authors: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-6077, USA.
authors: William
authors: W
authors: Motley
authors: MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK.
authors: Mary M
authors: MM
authors: Reilly
authors: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria.
authors: Wilfried
authors: W
authors: Renner
authors: Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
authors: Sabine
authors: S
authors: Rudnik-Schöneborn
authors: Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich 80336, Germany.
authors: Beate
authors: B
authors: Schlotter-Weigel
authors: 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.
authors: Andreas C
authors: AC
authors: Themistocleous
authors: Neurology Department, Ulm University, Ulm 89081, Germany.
authors: Jochen H
authors: JH
authors: Weishaupt
authors: Neurology Department, Ulm University, Ulm 89081, Germany.
authors: Albert C
authors: AC
authors: Ludolph
authors: Institute of Human Genetics, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Neuherberg 85764, Germany.
authors: Thomas
authors: T
authors: Wieland
authors: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: Feifei
authors: F
authors: Tao
authors: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: Lisa
authors: L
authors: Abreu
authors: 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.
authors: Reinhard
authors: R
authors: Windhager
authors: Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich 80336, Germany.
authors: Manuela
authors: M
authors: Zitzelsberger
authors: 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.
authors: Tim M
authors: TM
authors: Strom
authors: Department of Pharmacology and Therapeutics, University College Cork, Cork T12 YT57, Ireland; Department of Obstetrics, University of Leipzig, Leipzig 04103, Germany.
authors: Thomas
authors: T
authors: Walther
authors: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-6077, USA.
authors: Steven S
authors: SS
authors: Scherer
authors: Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: Stephan
authors: S
authors: Züchner
authors: Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Würzburg 97080, Germany.
authors: Rudolf
authors: R
authors: Martini
authors: Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich 80336, Germany. Electronic address: jan.senderek@med.uni-muenchen.de.
authors: Jan
authors: J
authors: Senderek
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D000483:Alleles; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000473:pathology*; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D003704:Dementia / Q000150:complications / Q000235:genetics; D059472:Exome / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D015260:Neprilysin / Q000032:analysis / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D019683:Penetrance; D011115:Polyneuropathies / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D012867:Skin / Q000378:metabolism; D013497:Sural Nerve
chemical_list: D016229:Amyloid beta-Peptides; D015260:Neprilysin