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

Michaela Auer-Grumbach; Stefan Toegel; Maria Schabhüttl; Daniela Weinmann; Catharina Chiari; David L H Bennett; Christian Beetz; Dennis Klein; Peter M Andersen; Ilka Böhme; Regina Fink-Puches; Michael Gonzalez; Matthew B Harms; William Motley; Mary M Reilly; Wilfried Renner; Sabine Rudnik-Schöneborn; Beate Schlotter-Weigel; Andreas C Themistocleous; Jochen H Weishaupt; Albert C Ludolph; Thomas Wieland; Feifei Tao; Lisa Abreu; Reinhard Windhager; Manuela Zitzelsberger; Tim M Strom; Thomas Walther; Steven S Scherer; Stephan Züchner; Rudolf Martini; Jan Senderek

doi:10.1016/j.ajhg.2016.07.008

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

Journal article

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

Michaela Auer-Grumbach, Stefan Toegel, Maria Schabhüttl, Daniela Weinmann, Catharina Chiari, David L H Bennett, Christian Beetz, Dennis Klein, Peter M Andersen, Ilka Böhme, …

American journal of human genetics, Vol.99(3), pp.607-623

2016-09-01

DOI: https://doi.org/10.1016/j.ajhg.2016.07.008

PMCID: PMC5011077

PMID: 27588448

Abstract

Skin - metabolism

Humans

Middle Aged

Databases, Genetic

Dementia - genetics

Mutation, Missense - genetics

Charcot-Marie-Tooth Disease - genetics

Adipose Tissue - metabolism

Aging - genetics

Polyneuropathies - complications

DNA Mutational Analysis

Amyloid beta-Peptides - metabolism

Aged, 80 and over

Adult

Neprilysin - genetics

Sural Nerve

Charcot-Marie-Tooth Disease - complications

Neprilysin - blood

Neprilysin - analysis

Penetrance

Charcot-Marie-Tooth Disease - pathology

Mutation - genetics

Exome - genetics

Neprilysin - deficiency

Animals

Dementia - complications

Polyneuropathies - pathology

Axons - pathology

Age of Onset

Alleles

Polyneuropathies - genetics

Heterozygote

Aged

Mice

Genes, Dominant - genetics

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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.253 Nerve Disorders; 1.253.1972 Charcot-Marie-Tooth Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies
Creators: Michaela Auer-Grumbach - Department of Orthopaedics, Medical University of Vienna, Vienna 1090, Austria. Electronic address: michaela.auer-grumbach@meduniwien.ac.at
Stefan Toegel - 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
Maria Schabhüttl - Department of Orthopaedics, Medical University of Vienna, Vienna 1090, Austria
Daniela Weinmann - 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
Catharina Chiari - 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
David L H Bennett - Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK
Christian Beetz - Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena 07745, Germany
Dennis Klein - Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Würzburg 97080, Germany
Peter M Andersen - Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå 901 85, Sweden
Ilka Böhme - Department of Pediatric Surgery, University of Leipzig, Leipzig 04103, Germany
Regina Fink-Puches - Department of Dermatology, Medical University of Graz, Graz 8036, Austria
Michael Gonzalez - The Genesis Project Inc., Miami, FL 3136, USA
Matthew B Harms - Department of Neurology, Columbia University, New York, NY 10032, USA
William Motley - Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-6077, USA
Mary M Reilly - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK
Wilfried Renner - Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria
Sabine Rudnik-Schöneborn - Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria
Beate Schlotter-Weigel - Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich 80336, Germany
Andreas C Themistocleous - 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
Jochen H Weishaupt - Neurology Department, Ulm University, Ulm 89081, Germany
Albert C Ludolph - Neurology Department, Ulm University, Ulm 89081, Germany
Thomas Wieland - Institute of Human Genetics, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Neuherberg 85764, Germany
Feifei Tao - Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Lisa Abreu - Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Reinhard Windhager - 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
Manuela Zitzelsberger - Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich 80336, Germany
Tim M Strom - 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
Thomas Walther - Department of Pharmacology and Therapeutics, University College Cork, Cork T12 YT57, Ireland; Department of Obstetrics, University of Leipzig, Leipzig 04103, Germany
Steven S Scherer - Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-6077, USA
Stephan Züchner - Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Rudolf Martini - Department of Neurology, Developmental Neurobiology, University Hospital Würzburg, Würzburg 97080, Germany
Jan Senderek - Friedrich-Baur-Institute, Ludwig Maximilians University Munich, Munich 80336, Germany. Electronic address: jan.senderek@med.uni-muenchen.de
Publication Details: American journal of human genetics, Vol.99(3), pp.607-623
Publisher: United States
Grant note: P 27634 / Austrian Science Fund FWF R01 NS075764 / NINDS NIH HHS U54 NS065712 / NINDS NIH HHS
Academic Unit: Leadership Department; John P. Hussman Institute for Human Genomics; Miller School of Medicine
Language: English
Resource Type: Journal article
PMID: 27588448
PMCID: PMC5011077
Record Identifier: 991031578035902976